This invention is in the field of preventing and/or treating cardiovascular disease, and specifically relates to compounds, compositions and methods for preventing and/or treating atherosclerosis and other coronary artery disease. More particularly, the invention relates to substituted pyridine compounds that inhibit cholesteryl ester transfer protein (CETP), also known as plasma lipid transfer protein-I.
Numerous studies have demonstrated that a low plasma concentration of high density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis (Barter and Rye, Atherosclerosis, 121, 1-12 (1996)). HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids. The other classes of lipoproteins found in the blood are low density lipoprotein (LDL) and very low density lipoprotein (VLDL). Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol would be therapeutically beneficial for the treatment of atherosclerosis and other diseases associated with accumulation of lipid in the blood vessels. These diseases include, but are not limited to, coronary heart disease, peripheral vascular disease, and stroke.
Atherosclerosis underlies most coronary artery disease (CAD), a major cause of morbidity and mortality in modern society. High LDL cholesterol (above 180 mg/dl) and low HDL cholesterol (below 35 mg/dl) have been shown to be important contributors to the development of atherosclerosis. Other diseases, such as peripheral vascular disease, stroke, and hypercholesterolaemia are negatively affected by adverse HDL/LDL ratios. Inhibition of CETP by the subject compounds are shown to effectively modify plasma HDL/LDL ratios, and to check the progress and/or formation of these diseases.
CETP is a plasma protein that facilitates the movement of cholesteryl esters and triglycerides between the various lipoproteins in the blood (Tall, J. Lipid Res., 34, 1255-74 (1993)). The movement of cholesteryl ester from HDL to LDL by CETP has the effect of lowering HDL cholesterol. It therefore follows that inhibition of CETP should lead to elevation of plasma HDL cholesterol and lowering of plasma LDL cholesterol, thereby providing a therapeutically beneficial plasma lipid profile (McCarthy, Medicinal Res. Revs., 13, 139-59 (1993)). This exact phenomenon was first demonstrated by Swenson et al., (J. Biol. Chem., 264, 14318 (1989)) with the use of a monoclonal antibody that specifically inhibited CETP. In rabbits, the antibody caused an elevation of the plasma HDL cholesterol and a decrease in LDL cholesterol. Son et al. (Biochim. Biophys. Acta 795, 743-480 (1984)) describes proteins from human plasma that +inhibit CETP. U.S. Pat. No. 5,519,001, issued to Kushwaha et al., describes a 36 amino acid peptide derived from baboon apo C-1 that inhibits CETP activity.
There have been several reports of compounds that act as CETP inhibitors. Barrett et al. (J. Am. Chem. Soc., 188, 7863-63 (1996)) describes cyclopropane-containing CETP inhibitors. Pietzonka et al. (Bioorg. Med. Chem. Lett, 6, 1951-54 (1996)) describe phosphonate-containing analogs of cholesteryl ester as CETP inhibitors. Coval et al. (Bioorg. Med. Chem. Lett., 5, 605-610 (1995)) describe Wiedendiol-A and -B, and related sesquiterpene compounds, as CETP inhibitors. Lee et al. (J. Antibiotics, 49, 693-96 (1996)) describe CETP inhibitors derived from an insect fungus. Busch et al. (Lipids, 25, 216-220, (1990)) describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and Zilversmit (J. Lipid Res., 35, 836-47 (1982)) describe that p-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP. Bisgaier et al. (Lipids, 29, 811-8 (1994) describe 4-phenyl-5-tridecyl-4H-1,2,4-triazole-thiol as a CETP inhibitor.
A number of substituted pyridine compounds are known. For example, U.S. Pat. Nos. 4,609,399, 4,655,816; 4,692,184; 4,698,093; 4,789,395; 4,885,026; 4,936,905; 4,988,384; 5,037,469; 5,125,961; 5,129,943; 5,156,670; 5,169,432; and 5,260,262 each disclose novel substituted pyridines which are useful as herbicides and herbicide intermediates. No pharmacologic properties for the substituted pyridines are recited in these patents. Except as set forth below, the literature does not describe substituted pyridines as inhibitors of CETP.
Connolly et al. (Biochem. Biophys. Res. Comm. 223, 42-47 (1996)), describe 4,4xe2x80x2-dithiopyridine, 2,2xe2x80x2-dithiopyridine, 6,6xe2x80x2-dithionicotinic acid and 2,2xe2x80x2-dithiobis (pyridine-N-oxide) as CTEP inhibitors. The isolated pyridine compounds tested by Connolly et al. were, at best, inhibitory only after a 16 hour pre-incubation period and would not be useful in situations requiring rapid and potent inhibition. Connolly et al. also neither addressed whether substitution of the reported pyridines would increase their potency nor suggested the testing or use of specific substituted pyridines.
European Patent Application 796 846 A1 describes certain 2-aryl-substituted pyridines for use in the treatment of lipoproteinaemia and hyperlipoproteinaemia.
European Patent Application 818 197 A1 describes certain 2-aryl-substituted pyridines for use in the treatment of hyperlipoproteinaemia and atherosclerosis.
U.S. Pat. No. 4,925,852 describes 3-demethylmevalonic acid derivatives for use as inhibitors of cholesterol biosynthesis.
U.S. Pat. No. 5,169,857 describes 7-(polysubstituted pyridyl)-hept-6-endates for use in the treatment of hyperproteinaemia, lipoproteinaemia or arteriosclerosis.
WO 98/04528 describes certain 4-aryl-pyridyl compounds as anti-hypercholesterolemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents.
The present invention is directed to a method for administering to a subject a therapeutically effective amount of a substituted pyridine of Formula I: 
wherein:
R2 and R6 are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R2 and R6 is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;
R3 is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl,
xe2x80x94CHO,
xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen, alkyl and cyanoalkyl; and 
xe2x80x83wherein
R15a is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy, and
R16a is selected from the group consisting of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, and heterocyclyl, arylalkoxy, trialkylsilyloxy;
R4 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino, diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl,
xe2x80x94OC(O)N(R8aR8b), wherein R8a and R8b are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,
xe2x80x94SO2R9, wherein R9 is selected from the group consisting of hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,
xe2x80x94OP(O)(OR10a)(OR10b), wherein R10a and R10b are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and
xe2x80x94OP(S)(OR11a)(OR11b), wherein R11a and R11b are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
R5 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl, arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl, alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl, heterocyclyloxyalkenyl, cyano, hydroxymethyl,
xe2x80x94CO2R14,
wherein R14 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; 
xe2x80x83wherein
R15b is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy, and
R16b is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, and trialkylsilyloxy; 
wherein R17 and R18 are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; 
wherein R19 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, xe2x80x94SR20, xe2x80x94OR21, and xe2x80x94R22CO2R23, wherein
R20 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl, alkylheteroarylamino, arylheteroarylamino,
R21 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,
R22 is selected from the group consisting of alkylene or arylene, and
R23 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
wherein R24 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, aralkenyl, and aralkynyl; 
wherein R25 is heterocyclylidenyl; 
wherein R26 and R27 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
wherein R28 and R29 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
wherein R30 and R31 are independently alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and 
wherein R32 and R33 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
wherein R36 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl and heterocyclyl; 
wherein R37 and R38 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
xe2x80x83wherein
R39 is selected from the group consisting of hydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio, and
R40 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy, heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio;
xe2x80x94Nxe2x95x90R41,
wherein R41 is heterocyclylidenyl; 
xe2x80x83wherein
R42 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and
R43 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, and haloheterocyclyl; 
wherein R44 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
xe2x80x94Nxe2x95x90Sxe2x95x90O;
xe2x80x94Nxe2x95x90Cxe2x95x90S;
xe2x80x94Nxe2x95x90Cxe2x95x90O;
xe2x80x94N3;
xe2x80x94SR45,
wherein R45 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl, aminocarbonylaryl, aminocarbonylheteroaryl, and aminocarbonylheterocyclyl, xe2x80x94SR46, and xe2x80x94CH2R47,
wherein R46 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and
R47 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; and 
xe2x80x83wherein
R48 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and
R49 is selected from the group consisting of alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl; 
wherein R50 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy; 
wherein R51 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl; and 
wherein R53 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
or a pharmaceutically acceptable salt or tautomer thereof,
provided that when R5 is selected from the group consisting of heterocyclylalkyl and heterocyclylalkenyl, then the heterocyclyl radical of the corresponding heterocyclylalkyl or heterocyclylalkenyl is other than a xcex4-lactone; and
provided that when R4 is aryl, heteroaryl or heterocyclyl, and one of R2 and R6 is trifluoromethyl, then the other of R2 and R6 is difluoromethyl.
In another embodiment, the method involves the administration of a therapeutically effective amount of a substituted pyridine of Formula IA wherein: 
R2 and R6 are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R2 and R6 is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;
R3 is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl,
xe2x80x94CO2R7,
wherein R7 is selected from the group consisting of hydrogen, alkyl and cyanoalkyl; and 
xe2x80x83wherein
R15a is a is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, and
R16a is selected from the group consisting of alkyl, aryl and heteroaryl;
R4 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,
xe2x80x94OC(O)N(R8)2, wherein R8 is aryl,
xe2x80x94SO2R9, wherein R9 is aryl,
xe2x80x94OP(O)(OR10)2, wherein R10 is alkyl, and
xe2x80x94OP(S)(OR11)2, wherein R11 is alkyl;
R5 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, haloalkyl, alkynyl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylcarbonyloxyalkyl, heterocyclylalkyl, alkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, cyano, hydroxymethyl,
xe2x80x94CO2R14,
wherein R14 is alkyl; 
xe2x80x83wherein
R15b is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio and alkoxy, and
R16b is selected from the group consisting of alkyl, aryl and heteroaryl; 
wherein R17 and R18 are independently alkyl; 
wherein R19 is selected from the group consisting of aryl, heteroaryl, xe2x80x94SR20, xe2x80x94OR21, and xe2x80x94R22CO2R23,
wherein R20 is selected from the group consisting of alkyl, aryl and aminoalkyl,
R21 is aryl,
R22 is alkylene, and
R23 is alkyl; 
wherein R24 is selected from the group consisting of hydrogen, unsubstituted alkyl, and aralkyl; 
wherein R25 is heterocyclylidenyl; 
wherein R26 and R27 are independently alkyl; 
wherein R28 and R29 are independently alkyl; 
wherein R30 and R31 are independently alkoxy; 
xe2x80x83wherein
R32 is selected from the group consisting of hydrogen and alkyl, and
R33 is alkyl; 
wherein R37 and R38 are independently alkyl; 
xe2x80x83wherein
R39 is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and
R40 is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio; 
xe2x80x83wherein
R42 is selected from the group consisting of hydrogen and alkyl, and
R43 is selected from the group consisting of cycloalkyl, chlorinated alkyl and substituted heteroaryl; 
wherein R45 is selected from the group consisting of hydrogen, alkyl, haloalkyl, heterocyclyl, aralkyl, heteroaralkyl, alkylthioalkyl, aminocarbonylalkyl, xe2x80x94SR46, and xe2x80x94CH2R47,
wherein R46 is selected from the group consisting of aryl and heteroaryl, and
R47 is selected from the group consisting of aryl and heteroaryl; and 
xe2x80x83wherein
R48 is selected from the group consisting of hydrogen and alkyl, and
R49 is selected from the group consisting of alkoxy and haloalkyl; 
wherein R50 is selected from the group consisting of alkyl, alkoxy, aryl and heteroaryl; 
wherein R51 is selected from the group consisting of haloalkyl and alkyl; and 
wherein R53 is aryl;
or a pharmaceutically acceptable salt or tautomer thereof,
provided that when R5 is heterocyclylalkyl or heterocyclylalkenyl, then the heterocyclyl radical is other than a xcex4-lactone and the alkyl or alkenyl radical is other than xe2x80x94CH2CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94.
Preferably, the immediately preceding embodiment involves the administration of a substituted pyridine of Formula IA as described above wherein:
when R2 is difluoromethyl, 
xe2x80x83R6 is trifluoromethyl and R19 is the heteroaryl 1-pyrazolyl, then R4 is other than isopropylamino; and
when R2 is difluoromethyl, R3 is xe2x80x94CO2CH3, R5 is the unsubstituted heterocyclyl 2-(4,5-dihydro-oxazolyl), and R6 is trifluoromethyl, then R4 is other than cyclopropylmethyl; and
when R2 and R6 are selected from the group consisting of difluoromethyl and trifluoromethyl, R3 is selected from the group consisting of xe2x80x94CO2H and xe2x80x94CO2C2H5, and R5 is cyano, then R4 is other than ethyl or xe2x80x94CHxe2x95x90C(CH3)2; and
when R2 is methyl, 
xe2x80x83is methyl, and R24 is xe2x80x94C(O)NHCH2-(4-chlorophenyl), then R4 is other than hydrogen; and
when R2 is methyl, R3 and R5 are xe2x80x94CO2C2H5, R4 is i-propoxy, then R6 is other than methyl; and
when R2 is difluoromethyl, R4 is xe2x80x94CHxe2x95x90C(CH3)2, R5 is xe2x80x94CO2CH3, and R6 is trifluoromethyl, then R3 is other than xe2x80x94CO2H; and
when R2 is methyl, R4 is hydrogen, R4 is xe2x80x94CO2C2H5 and R6 is methyl, then R3 is other than xe2x80x94CO2C2H5;
when R2 is difluoromethyl, R4 is hydrogen, R5 is xe2x80x94CO2C2H5, and R6 is trifluoromethyl, then R3 is other than xe2x80x94CO2C2H5;
when R2 is difluoromethyl, R4 is xe2x80x94CH2SCH3, R5 is xe2x80x94CO2C2H5, and R6 is trifluoromethyl, then R3 is other than xe2x80x94CO2H;
when R2 is trifluoromethyl, R3 is xe2x80x94CO2CH3, R4 is isobutyl, R5 is xe2x80x94CO2CH3, then R6 is other than methyl;
when R2 is difluoromethyl, R4 is selected from the group consisting of isopropyl and isobutyl, R5 is xe2x80x94CO2R14, R6 is trifluoromethyl, and R14 is alkyl, then R3 is other than amido;
when R2 is selected from the group consisting of hydroxy and trifluoromethyl, R4 and R5 are hydrogen, and R6 is selected from the group consisting of methyl and trifluoromethyl, then R3 is other than xe2x80x94CO2H;
when R2 is selected from the group consisting of methyl, difluoromethyl and trifluoromethyl, R3 is xe2x80x94CO2CH3, R5 is hydrogen, and R6 is selected from the group consisting of methyl and trifluoromethyl, then R4 is other than alkyl or arylcarbonyloxy;
when R2 is trifluoromethyl, R3 is xe2x80x94CO2C2H5, R4 is hydroxy, and R5 is hydrogen, then R6 is other than hydrogen; and
when R2 is trifluoromethyl, R3 is selected from the group consisting of xe2x80x94CO2H and xe2x80x94CO2C2H5, R5 is methyl, and R6 is selected from the group consisting of hydrogen and trifluoromethyl, then R4 is other than hydroxy.
Among the objects of the present method are the inhibition of CTEP in vivo; the treatment or prevention of coronary artery disease; the treatment or prevention of atherosclerosis; the alteration of the LDL/HDL ratio or profile in plasma; and the elevation of HDL levels in plasma.
The present invention is additionally directed to the novel substituted pyridines of Formula IIA: 
wherein:
R2 and R6 are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R2 and R6 is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;
R3 is selected from the group consisting of arylcarbonyl, heteroarylcarbonyl, hydroxymethyl, arylalkoxyalkyl, trialkylsilyloxyalkyl,
xe2x80x94CHO,
xe2x80x94CO2R7,
wherein R7 is selected from the group consisting of hydrogen and alkyl; and 
xe2x80x83wherein
R15a is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, and
R16a is selected from the group consisting of alkyl, haloalkyl, alkenyl, aryl and heteroaryl;
R4 is selected from the group consisting of hydrogen, hydroxy, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, alkoxy, thio, trialkylsilyl, alkylamino, and xe2x80x94OC(O)N(R8)2, wherein R8 is aryl;
R5 is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aralkyl, alkoxy, aryloxy, cycloalkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, arylcarbonyloxyalkyl, pyrrolyl, substituted pyrrolidinyl, hydroxymethyl, arylalkoxyalkyl, and trialkylsilyloxyalkyl,
xe2x80x94CO2R14,
wherein R14 is alkyl; 
xe2x80x83wherein R15b is selected from the group consisting of hydroxy, halogen, alkoxy, and alkylthio, aroyloxy, and alkylsulfonyloxy, and
R16b is selected from the group consisting of alkyl, alkenyl, aryl, and heteroaryl; 
wherein R17 and R18 are independently alkyl; 
wherein R19 is aryl, heteroaryl, xe2x80x94SR20, and xe2x80x94OR21,
wherein R20 is selected from the group consisting of aryl, heteroaryl and aminoalkyl, and
R21 is selected from the group consisting of aryl and heteroaryl; 
wherein R28 and R29 are independently alkyl; 
wherein R30 and R31 are independently alkoxy;
xe2x80x94Cxe2x89xa1Cxe2x80x94Si(R36)3,
wherein R36 is alkyl; 
xe2x80x83wherein
R37 is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and
R38 is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio;
provided that when R37 is hydrogen, then R38 is selected from the group consisting of haloalkyl, cycloalkyl, and heterocyclylalkoxy; 
xe2x80x83wherein
R42 is selected from the group consisting of hydrogen and alkyl, and
R43 is substituted heteroaryl; 
wherein R44 is selected from the group consisting of aryl and heteroaryl;
xe2x80x94SR45,
wherein R45 is selected from the group consisting of haloalkyl, heterocyclyl, alkylthioalkyl, aminocarbonylalkyl, xe2x80x94SR46, and xe2x80x94CH2R47,
wherein R46 is selected from the group consisting of aryl and heteroaryl, and
R47 is selected from the group consisting of methylenedioxyphenyl, pyridyl, quinolinyl, tetrahydronaphthyl and benzodioxanyl; 
xe2x80x83wherein
R48 is selected from the group consisting of hydrogen and alkyl, and
R49 is selected from the group consisting of alkoxy and haloalkyl; 
wherein R50 is selected from the group consisting of alkyl, alkoxy, and heteroaryl; and 
wherein R51 is haloalkyl;
or a pharmaceutically acceptable salt or tautomer thereof,
provided that:
when R2 is selected from the group consisting of difluoromethyl and trifluoromethyl, R3 is selected from the group consisting of xe2x80x94CO2H, xe2x80x94CO2CH3 and xe2x80x94CO2C2H5, R5 is hydrogen, and R6 is selected from the group consisting of hydrogen and trifluoromethyl, then R4 is other than hydrogen, hydroxy or iso-butyl; provided further that when R2, R3 and R5 are as defined above, and R4 is selected from the group consisting of alkylamino and alkoxy, then R6 is hydrogen;
when R2 is selected from the group consisting of fluorinated methyl and chlorofluorinated methyl, R3 is selected from the group consisting of hydroxymethyl and CO2R7, R5 is selected from the group consisting of hydroxymethyl and CO2R14, R6 is selected from the group consisting of alkyl, fluorinated methyl and chlorofluorinated methyl, and R7 and R14 are independently alkyl, then R4 is other than alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, alkylamino and heteroarylalkyl;
when R2 is selected from the group consisting of difluoromethyl and trifluoromethyl, R3 is xe2x80x94CO2C2H5, R4 is hydrogen, and R5 is xe2x80x94CO2C2H5, then R6 is other than trifluoromethyl;
when R2 is trifluoromethyl, R3 is CO2R7, R5 is methyl, and R6 is selected from the group consisting of fluorinated methyl, fluorinated ethyl and chlorofluorinated methyl, then R4 is other than alkoxy, alkylamino and hydroxy;
when R4 is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl, R3 is xe2x80x94CO2R7, and R7 is alkyl, then R5 is other than arylcarbonyl, heteroarylcarbonyl or 
wherein R16b is alkyl when R15b is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, or wherein R16b is aryl or heteroaryl when R15b is hydroxy;
when R4 is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl, R5 is xe2x80x94CO2R14, and R14 is alkyl, then R3 is other than arylcarbonyl, heteroarylcarbonyl or 
wherein R16a is alkyl when R15a is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, or wherein R16a is aryl or heteroaryl when R15a is hydroxy; and
when R2 and R6 are independently selected from fluorinated methyl and chlorofluorinated methyl, R3 is CO2R7, R5 is hydroxy, alkoxy or aryloxy, then R4 is other than hydrogen, hydroxy, alkyl or alkoxy; and
when R4 is aryl and one of R2 and R6 is trifluoromethyl, then the other of R2 and R6 is difluoromethyl.
Novel Methods
The present invention comprises a method for the treatment or prophylaxis of CTEP-mediated disorders (such as coronary artery disease) in a subject, comprising administering to the subject having such a disorder a therapeutically-effective amount of a compound of Formula I: 
wherein:
R2 and R6 are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R2 and R6 is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;
R3 is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl,
xe2x80x94CHO,
xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen, alkyl and cyanoalkyl; and 
xe2x80x83wherein
R15a is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy, and
R16a is selected from the group consisting of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, and heterocyclyl, arylalkoxy, trialkylsilyloxy;
R4 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino, diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl,
xe2x80x94OC(O)N(R8aR8b), wherein R8a and R8b are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,
xe2x80x94SO2R9, wherein R9 is selected from the group consisting of hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,
xe2x80x94OP(O)(OR10a)(OR10b), wherein R10a and R10b are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and
xe2x80x94OP(S)(OR11a)(OR11b), wherein R11a and R11b are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
R5 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl, arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl, alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl, heterocyclyloxyalkenyl, cyano, hydroxymethyl,
xe2x80x94CO2R14,
wherein R14 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; 
xe2x80x83wherein
R15b is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy, and
R16b is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, and trialkylsilyloxy; 
wherein R17 and R18 are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; 
wherein R19 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, xe2x80x94SR20, xe2x80x94OR21, and xe2x80x94R22CO2R23, wherein
R20 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl, alkylheteroarylamino, arylheteroarylamino,
R21 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,
R22 is selected from the group consisting of alkylene or arylene, and
R23 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
wherein R24 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, aralkenyl, and aralkynyl; 
wherein R25 is heterocyclylidenyl; 
wherein R26 and R27 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
wherein R28 and R29 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
wherein R30 and R31 are independently alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and 
wherein R32 and R33 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
wherein R36 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl and heterocyclyl; 
wherein R37 and R38 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
xe2x80x83wherein
R39 is selected from the group consisting of hydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio, and
R40 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy, heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio;
xe2x80x94Nxe2x95x90R41,
wherein R41 is heterocyclylidenyl; 
xe2x80x83wherein
R42 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and
R43 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, and haloheterocyclyl; 
wherein R44 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
xe2x80x94Nxe2x95x90Sxe2x95x90O;
xe2x80x94Nxe2x95x90Cxe2x95x90S;
xe2x80x94Nxe2x95x90Cxe2x95x90O;
xe2x80x94N3;
xe2x80x94SR45,
wherein R45 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl, aminocarbonylaryl, aminocarbonylheteroaryl, and aminocarbonylheterocyclyl, xe2x80x94SR46, and xe2x80x94CH2R47,
wherein R46 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and
R47 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; and 
xe2x80x83wherein
R48 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and
R49 is selected from the group consisting of alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl; 
wherein R50 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy; 
wherein R51 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl; and 
wherein R53 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
or a pharmaceutically acceptable salt or tautomer thereof,
provided that when R5 is selected from the group consisting of heterocyclylalkyl and heterocyclylalkenyl, then the heterocyclyl radical of the corresponding heterocyclylalkyl or heterocyclylalkenyl is other than a xcex4-lactone; and
provided that when R4 is aryl, heteroaryl or heterocyclyl, and one of R2 and R6 is trifluoromethyl, then the other of R2 and R6 is difluoromethyl.
In another embodiment, the method comprises the administration of a therapeutically effective amount of a substituted pyridine of Formula IA: 
wherein:
R2 and R6 are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R2 and R6 is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;
R3 is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl,
xe2x80x94CO2R7,
wherein R7 is selected from the group consisting of hydrogen, alkyl (preferably methyl or ethyl) and cyanoalkyl; and 
xe2x80x83wherein
R15a is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, and
R16a is selected from the group consisting of alkyl, aryl and heteroaryl;
R4 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,
xe2x80x94OC(O)N(R8)2, wherein R8 is aryl,
xe2x80x94SO2R9, wherein R9 is aryl,
xe2x80x94OP(O)(OR10)2, wherein R11 is alkyl, and
xe2x80x94OP(S)(OR11)2, wherein R11 is alkyl;
R5 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, haloalkyl, alkynyl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylcarbonyloxyalkyl, heterocyclylalkyl, alkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, cyano, hydroxymethyl,
xe2x80x94CO2R14,
wherein R14 is alkyl; 
xe2x80x83wherein
R15b is selected from the group consisting of hydroxy, hydrogen, alkylthio and alkoxy, and
R16b is selected from the group consisting of alkyl, aryl and heteroaryl; 
wherein R17 and R18 are independently alkyl; 
wherein R19 is selected from the group consisting of aryl, heteroaryl, xe2x80x94SR20, xe2x80x94OR21, and xe2x80x94R22CO2R23,
wherein R20 is selected from the group consisting of alkyl, aryl and aminoalkyl,
R21 is aryl,
R22 is alkylene, and
R23 is alkyl; 
wherein R24 is selected from the group consisting of hydrogen, unsubstituted alkyl, and aralkyl; 
wherein R25 is heterocyclylidenyl; 
wherein R26 and R27 are independently alkyl; 
wherein R28 and R29 are independently alkyl; 
wherein R30 and R31 are independently alkoxy; 
xe2x80x83wherein
R32 is selected from the group consisting of hydrogen and alkyl, and
R33 is alkyl; 
wherein R36 is alkyl; 
wherein R37 and R38 are independently alkyl; 
xe2x80x83wherein
R39 is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and
R40 is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio;
xe2x80x94Nxe2x95x90R41, wherein R41 is heterocyclylidenyl; 
xe2x80x83wherein
R42 is selected from the group consisting of hydrogen and alkyl, and
R43 is selected from the group consisting of cycloalkyl, chlorinated alkyl and substituted heteroaryl; 
wherein R44 is heteroaryl;
xe2x80x94Nxe2x95x90Sxe2x95x90O;
xe2x80x94Nxe2x95x90Cxe2x95x90S;
xe2x80x94Nxe2x95x90Cxe2x95x90O;
xe2x80x94N3;
xe2x80x94SR45,
wherein R45 is selected from the group consisting of hydrogen, alkyl, haloalkyl, heterocyclyl, aralkyl, heteroaralkyl, alkylthioalkyl, aminocarbonylalkyl, xe2x80x94SR46, and xe2x80x94CH2R47,
wherein R46 is selected from the group consisting of aryl and heteroaryl, and
R47 is selected from the group consisting of aryl and heteroaryl; and 
xe2x80x83wherein
R48 is selected from the group consisting of hydrogen and alkyl, and
R49 is selected from the group consisting of alkoxy and haloalkyl; 
wherein R50 is selected from the group consisting of alkyl, alkoxy, aryl and heteroaryl; 
wherein R51 is selected from the group consisting of haloalkyl and alkyl; and 
wherein R53 is aryl;
or a pharmaceutically acceptable salt or tautomer thereof,
provided that when R5 is selected from the group consisting of heterocyclylalkyl and heterocyclylalkenyl, then the heterocyclyl radical is other than a xcex4-lactone and the alkyl or alkenyl radical is other than xe2x80x94CH2CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94.
Preferably, the immediately preceding embodiment involves the administration of a substituted pyridine of Formula IA as described above wherein:
when R2 is difluoromethyl, 
xe2x80x83R6 is trifluoromethyl, and R19 is the heteroaryl 1-pyrazolyl, then R4 is selected from the group consisting of hydrogen, hydroxy, halogen, alkoxy, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, trialkylsilyl,
xe2x80x94OC(O)N(R8)2, wherein R8 is aryl,
xe2x80x94SO2R9, wherein R9 is aryl,
xe2x80x94OP(O)(OR10)2, wherein R10 is alkyl, and
xe2x80x94OP(S)(OR11)2, wherein R11 is alkyl; and
when R2 is difluoromethyl, R3 is xe2x80x94CO2CH3, R5 is the heterocyclyl 2-(4,5-dihydro-oxazolyl), and R6 is trifluoromethyl, then R4 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,
xe2x80x94OC(O)N(R8)2, wherein R8 is aryl,
xe2x80x94SO2R9, wherein R9 is aryl,
xe2x80x94OP(O)(OR10)2, wherein R10 is alkyl, and
xe2x80x94OP(S)(OR11)2, wherein R11 is alkyl; and
when R2 and R6 are independently fluorinated methyl, R3 is xe2x80x94CO2R7, R5 is cyano, and R7 is selected from the group consisting of hydrogen and alkyl, then R4 is selected from the group consisting of hydrogen, hydroxy, halogen, cycloalkyl, haloalkyl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,
xe2x80x94OC(O)N(R8)2, wherein R8 is aryl,
xe2x80x94SO2R9, wherein R9 is aryl,
xe2x80x94OP(O)(OR10)2, wherein R10 is alkyl, and
xe2x80x94OP(S)(OR11)2, wherein R11 is alkyl; and
when R2 is methyl, 
xe2x80x83is methyl, and R24 is aralkyl, then R4 is selected from the group consisting of hydroxy, halogen, alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,
xe2x80x94OC(O)N(R8)2, wherein R8 is aryl,
xe2x80x94SO2R9, wherein R9 is aryl,
xe2x80x94OP(O)(OR10)2, wherein R10 is alkyl, and
xe2x80x94OP(S)(OR11)2, wherein R11 is alkyl, and
when R2 is methyl, R3 and R5 are xe2x80x94CO2C2H5, and R4 is alkoxy, then R6 is selected from the group consisting of hydrogen, hydroxy, alkyl comprising at least two carbon atoms, fluorinated alkyl, chlorofluorinated alkyl, alkoxy, alkoxyalkyl, and alkoxycarbonyl,
when R2 is difluoromethyl, R3 is xe2x80x94CO2R7, R4 is alkenyl, R5 is CO2CH3, and R6 is trifluoromethyl, then R7 is selected from the group consisting of alkyl and cyanoalkyl,
when R2 is methyl, R4 is hydrogen, R5 is CO2C2H5, and R6 is methyl, then R3 is selected from the group consisting of hydroxy, amido and xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen, methyl, alkyl comprising at least three carbon atoms, and cyanoalkyl,
when R2 is difluoromethyl, R4 is hydrogen, R5 is CO2C2H5, and R6 is trifluoromethyl, then R3 is selected from the group consisting of hydroxy, amido and xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen, methyl, alkyl comprising at least three carbon atoms, and cyanoalkyl,
when R2 is difluoromethyl, R4 is alkylthioalkyl, R5 is xe2x80x94CO2C2H5, and R6 is trifluoromethyl, then R3 is selected from the group consisting of hydroxy, amido and xe2x80x94CO2R7, wherein R7 is selected from the group consisting of alkyl and cyanoalkyl,
when R2 is trifluoromethyl, R3 is xe2x80x94CO2CH3, R4 is alkyl, R5 is xe2x80x94CO2CH3, then R6 is selected from the group consisting of hydrogen, hydroxy, alkyl comprising at least two carbon atoms, fluorinated alkyl, chlorofluorinated alkyl, alkoxy, alkoxyalkyl, and alkoxycarbonyl,
when R2 is difluoromethyl, R4 is alkyl, R5 is xe2x80x94CO2R14, R6 is trifluoromethyl, and R14 is alkyl, then R3 is selected from the group consisting of hydroxy and xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen, alkyl and cyanoalkyl,
when R2 is selected from the group consisting of hydroxy and trifluoromethyl, R4 and R5 are hydrogen, and R6 is selected from the group consisting of methyl and trifluoromethyl, then R3 is selected from the group consisting of hydroxy, amido and xe2x80x94CO2R7, wherein R7 is selected from the group consisting of alkyl and cyanoalkyl,
when R2 is selected from the group consisting of methyl, difluoromethyl and trifluoromethyl, R3 is xe2x80x94CO2CH3, R5 is hydrogen, and R6 is selected from the group consisting of methyl and trifluoromethyl, then R4 is selected from the group consisting of hydrogen, hydroxy, halogen, cycloalkyl, alkenyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,
xe2x80x94OC(O)N(R8)2, wherein R8 is aryl,
xe2x80x94SO2R9, wherein R9 is aryl,
xe2x80x94OP(O)(OR10)2, wherein R10 is alkyl; and
xe2x80x94OP(S)(OR11)2, wherein R11 is alkyl; and
when R2 is trifluoromethyl, R3 is xe2x80x94CO2C2H5, R4 is hydroxy, and R5 is hydrogen, then R6 is selected from the group consisting of hydroxy, alkyl, fluorinated alkyl, alkoxy, alkoxyalkyl and alkoxycarbonyl; and
when R2 is trifluoromethyl, R3 is selected from the group consisting of xe2x80x94CO2H and xe2x80x94CO2C2H5, R5 is methyl, and R6 is selected from the group consisting of hydrogen and trifluoromethyl, then R4 is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,
xe2x80x94OC(O)N(R8)2, wherein R8 is aryl,
xe2x80x94SO2R9, wherein R9 is aryl,
xe2x80x94OP(O)(OR10)2, wherein R10 is alkyl, and
xe2x80x94OP(S)(OR11)2, wherein R11 is alkyl.
In another embodiment, the method comprises the administration of a therapeutically effective amount of a substituted pyridine of Formula IA as defined in one of the embodiments discussed above wherein:
R2 is selected from the group consisting of methyl and fluorinated methyl; and
R3 is xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen, methyl and ethyl.
Pharmaceutically Acceptable Salts
Also included in the family of compounds of Formulae I, IA and IB used in the method of the present invention (as well as in the family of novel compounds of Formula IIA and IIB discussed below) are the pharmaceutically-acceptable salts thereof. The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,. salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,Nxe2x80x2-dibenzylethylenediamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
Treatment of CETP-Mediated Disorders
The methods of this invention additionally can be used, for example: (i) to inhibit cholesteryl ester transfer protein (CETP) activity, (ii) to decrease the concentrations of low density lipoprotein (LDL) and/or raise the level of high density lipoprotein (HDL), or otherwise alter lipoprotein profiles, resulting in a therapeutically beneficial plasma lipid profile; (iii) for the primary and secondary treatment of coronary artery disease, myocardial infarction and agina; (iv) for the treatment of dyslipidemia (hypoalphalipoproteinaemia), hyperlipoproteinaemia (chylomicronemia and hyperapobetalipoproteinaemia), peripheral vascular disease, hypercholesterolemia, atherosclerosis, and other CETP-mediated disorders; (v) for the prophylactic treatment of subjects who are at risk of developing CETP-mediated disorders; and (vi) to lower the risk of atherosclerosis. The methods would be also useful in prevention of cerebral vascular accident (CVA) or stroke.
Besides being useful for human treatment, these methods are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
Without being limited to a specific theory, applicant hypothesizes that the CETP molecule contains one or more specific hydrophobic binding sites that can accommodate the substituted pyridines of the present invention. Binding of the substituted pyridine to these sites is sufficient to inhibit CETP. This binding is generally rapid and reversible.
It is additionally hypothesized that the CETP molecule contains a cysteine at or near these hydrophobic binding sites. Inhibition potency can be enhanced by selecting a substituted pyridine which is capable of undergoing a disulfide exchange with this cysteine. This disulfide exchange is time-dependent and irreversible. While inhibition potency may be enhanced as a result of this disulfide exchange, substituted pyridines which are effective inhibitors and which do not undergo the disulfide exchange may be more desirable given the generally irreversible nature of the disulfide exchange reaction.
It is further hypothesized that such disulfide-modified CETP molecules can aggregate, perhaps as a result of conformational changes induced by interaction with the substituted pyridine.
Additional Embodiments of Novel Methods
In another embodiment, the method comprises the administration of a therapeutically effective amount of a compound of Formula IA wherein:
R2 is fluorinated alkyl;
R3 is xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen and alkyl;
R4 is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl;
R5 is selected from the group consisting of:
heteroaryl (preferably 1-pyrrolyl); 
wherein R37 and R38 are independently alkyl; 
xe2x80x83wherein
R39 is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and
R40 is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio;
xe2x80x94Nxe2x95x90R41,
wherein R41 is heterocyclylidenyl; 
xe2x80x83wherein
R42 is selected from the group consisting of hydrogen and alkyl, and
R43 is selected from the group consisting of cycloalkyl, chlorinated alkyl, and heteroaryl; 
wherein R44 is heteroaryl (preferably substituted pyridyl);
xe2x80x94Nxe2x95x90Sxe2x95x90O;
xe2x80x94Nxe2x95x90Cxe2x95x90S;
xe2x80x94Nxe2x95x90Cxe2x95x90O; and
xe2x80x94N3; and
R6 is fluorinated alkyl;
or a pharmaceutically acceptable salt or tautomer thereof.
In still another embodiment, the method comprises the administration of a therapeutically effective amount of a compound of Formula IA wherein:
R2 is fluorinated alkyl;
R3 is xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen and alkyl;
R4 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, alkoxy and alkylthio;
R5 is selected from the group consisting of:
xe2x80x94SR45,
wherein R45 is selected from the group consisting of hydrogen, alkyl, haloalkyl, heterocyclyl, aralkyl, heteroaralkyl, aminocarbonylalkyl, alkylthioalkyl, xe2x80x94SR46, and xe2x80x94CH2R47,
wherein R46 is selected from the group consisting of aryl (preferably substituted aryl) and heteroaryl (preferably substituted pyridyl), and
R47 is selected from the group consisting of aryl and heteroaryl (R47 is preferably substituted aryl); and 
xe2x80x83wherein
R48 is selected from the group consisting of hydrogen and alkyl, and
R49 is selected from the group consisting of alkoxy and haloalkyl; 
wherein R50 is selected from the group consisting of alkyl, alkoxy, aryl and heteroaryl (preferably substituted heteroaryl); 
wherein R51 is selected from the group consisting of alkyl and haloalkyl; and 
wherein R53 is aryl; and
R6 is fluorinated alkyl;
or a pharmaceutically acceptable salt or tautomer thereof.
In still another embodiment, the method comprises the administration of a therapeutically effective amount of a compound of Formula IA wherein:
R2 is selected from the group consisting of alkyl and fluorinated alkyl;
R3 is xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen and alkyl;
R4 is selected from the group consisting of hydroxy, alkoxy, aralkoxy, alkoxycarbonyl, alkylthio, arylthio,
xe2x80x94OC(O)N(R8)2, wherein R8 is aryl,
xe2x80x94SO2R9, wherein R9 is aryl,
xe2x80x94OP(O)(OR10)2, wherein R10 is alkyl, and
xe2x80x94OP(S)(OR11)2, wherein R11 is alkyl;
R5 is selected from the group consisting of hydrogen, hydroxy, halogen, alkoxy, and aryloxy; and
R6 is selected from the group consisting of hydrogen, fluorinated alkyl and alkoxycarbonyl;
or a pharmaceutically acceptable salt or tautomer thereof,
provided that when R2 is trifluoromethyl, R3 is xe2x80x94CO2C2H5, R4 is hydroxy and R5 is hydrogen, then R6 is selected from the group consisting of fluorinated alkyl and alkoxycarbonyl.
In yet another preferred embodiment, the method comprises the administration of a therapeutically effective amount of a compound of Formula IA wherein:
R2 is fluorinated alkyl;
R3 is xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen, alkyl and cyanoalkyl;
R4 is selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, arylcarbonyloxy, arylthio, and alkylamino;
R5 is selected from the group consisting of alkyl, haloalkyl, alkynyl, heterocyclyl, heteroaryl, heterocyclylalkyl, arylcarbonyloxyalkyl, alkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, cyano, 
xe2x80x83wherein
R15a is selected from the group consisting of hydroxy, alkylthio and alkoxy, and
R16b is selected from the group consisting of alkyl and heteroaryl; 
wherein R17 and R18 are each alkyl; 
wherein R19 is selected from the group consisting of heteroaryl (preferably a substituted pyridyl), xe2x80x94SR20, xe2x80x94OR21, and xe2x80x94R22CO2R23,
wherein R20 is selected from the group consisting of alkyl, aryl (preferably substituted aryl) and aminoalkyl,
R21 is aryl (preferably substituted aryl),
R22 is alkylene, and
R23 is alkyl; 
wherein R24 is selected from the group consisting of hydrogen, unsubstituted alkyl, and aralkyl; 
wherein R25 is heterocyclylidenyl; 
wherein R26 and R27 are independently alkyl; 
wherein R28 and R29 are independently alkyl; 
wherein R30 and R31 are each alkoxy; 
wherein R32 is selected from the group consisting of hydrogen and alkyl, and R33 is alkyl; 
wherein R36 is alkyl; and
R6 is selected from the group consisting of hydrogen, fluorinated alkyl and alkoxy,
or a pharmaceutically acceptable salt or tautomer thereof,
provided that:
when R2 is difluoromethyl, 
xe2x80x83R6 is trifluoromethyl, and R19 is the heteroaryl 1-pyrazolyl, then R4 is selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, arylcarbonyloxy, and arylthio; and
when R2 is difluoromethyl, R3 is xe2x80x94CO2CH3, R5 is the heterocyclyl 2-(4,5-dihydro-oxazolyl), and R6 is trifluoromethyl, then R4 is selected from the group consisting of alkyl, alkoxy, cycloalkyl, arylcarbonyloxy, arylthio, and alkylamino; and
when R2 and R6 are independently fluorinated methyl, R3 is xe2x80x94CO2R7, R5 is cyano, and R7 is selected from the group consisting of hydrogen and alkyl, then R4 is selected from the group consisting of alkoxy, cycloalkyl, cycloalkylalkyl, arylcarbonyloxy, arylthio, and alkylamino.
In yet another embodiment, the method comprises the administration of a therapeutically effective amount of a compound of Formula IA wherein:
R2 is selected from the group consisting of hydroxy, alkyl, fluorinated alkyl, and alkoxyalkyl;
R3 is selected from the group consisting of hydroxy, amido, and xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen and alkyl;
R4 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, alkoxycarbonyl, aralkenyl, thio, alkylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, and trialkylsilyl;
R5 is CO2R14, wherein R14 is alkyl;
R6 is selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, and alkoxyalkyl;
or a pharmaceutically acceptable salt or tautomer thereof,
provided that:
when R2 is methyl, R3 is xe2x80x94CO2C2H5, R4 is alkoxy, and R5 is xe2x80x94CO2C2H5, then R6 is selected from the group consisting of hydrogen, hydroxy, alkyl comprising at least two carbon atoms, fluorinated alkyl, and alkoxyalkyl;
when R2 is difluoromethyl, R3 is xe2x80x94CO2R7, R4 is alkenyl, R5 is CO2CH3, and R6 is trifluoromethyl, then R7 is alkyl;
when R2 is methyl, R4 is hydrogen, R5 is CO2R14, R6 is methyl, and R14 is alkyl, then R3 is selected from the group consisting of hydroxy, amido and xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen, methyl, alkyl comprising at least three carbon atoms and cyanoalkyl;
when R2 is difluoromethyl, R4 is hydrogen, R5 is CO2R14, R6 is trifluoromethyl, and R14 is alkyl, then R3 is selected from the group consisting of hydroxy, amido and xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen, methyl, alkyl comprising at least three carbon atoms and cyanoalkyl;
when R2 is difluoromethyl, R4 is alkylthioalkyl, R5 is CO2C2H5, and R6 is methyl, then R3 is selected from the group consisting of hydroxy, amido and xe2x80x94CO2R7, wherein R7 is alkyl;
when R2 is trifluoromethyl, R3 is xe2x80x94CO2CH3, R4 is alkyl, and R5 is xe2x80x94CO2CH3, then R6 is selected from the group consisting of hydrogen, hydroxy, alkyl comprising two or more carbon atoms, fluorinated alkyl, and alkoxyalkyl; and
when R2 is difluoromethyl, R4 is alkyl, R5 is selected from the group consisting of xe2x80x94CO2CH3 and xe2x80x94CO2C2H5, and R6 is trifluoromethyl, then R3 is selected from the group consisting of hydroxy and xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen and alkyl.
In yet another embodiment, the method comprises the administration of a therapeutically effective amount of a compound of Formula IA which is selected from the compounds disclosed in Tables 1-8 below. While a number of the compounds disclosed in Tables 1-7 below either were specifically known or generically disclosed in the art as herbicides, they were not known to possess the pharmacologic properties of the present invention. Among the compounds of Tables 1-7 used in the method which were not previously specifically known or generically disclosed in the art as herbicides are those compounds identified with an asterisk.
In yet another embodiment, the method comprises the administration of a therapeutically effective amount of the compound of Formula IA wherein:
R2 is selected from the group consisting of alkyl and fluorinated alkyl;
R3 is selected from the group consisting of xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen and alkyl;
R4 is selected from the group consisting of alkyl, cycloalkyl, arylcarbonyloxy, thio, arylthio, and heterocyclylthio,
R5 is selected from the group consisting of alkyl, heterocyclyl, arylthioalkyl, heteroarylthioalkyl,
xe2x80x94CO2R14,
wherein R14 is alkyl; 
xe2x80x83wherein
R15b is hydroxy, and
R16b is heteroaryl; 
wherein R19 is xe2x80x94SR20, and R20 is alkyl; 
xe2x80x83wherein
R39 is alkoxy, and
R40 is haloalkyl;
xe2x80x94Nxe2x95x90R41,
wherein R41 is heterocyclylidenyl;
xe2x80x94Nxe2x95x90Sxe2x95x90O;
xe2x80x94SR45,
wherein R45 is selected from the group consisting of hydrogen, xe2x80x94SR46, and xe2x80x94CH2R47,
wherein R46 is selected from the group consisting of aryl and heteroaryl, and
R47 is selected from the group consisting of aryl and heteroaryl; and 
wherein R50 is selected from the group consisting of alkyl and alkoxy;
R6 is selected from the group consisting of alkyl and fluorinated alkyl;
or a pharmaceutically acceptable salt or tautomer thereof;
provided that:
when R2 is trifluoromethyl, R3 is CO2CH3, R4 is isobutyl, and R5 is xe2x80x94CO2CH3, then R6 is selected from the group consisting of alkyl comprising at least two carbon atoms and fluorinated alkyl.
In yet another embodiment, the method comprises the administration of a therapeutically effective amount of the compound of Formula IA which is selected from the compounds disclosed below:
Methyl 5-[(4-t-Butylphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl))-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 180);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(palmitoylthio)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 5);
Methyl 2-(Difluoromethyl)-5-(methoxycarbonylthio)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 6);
Diethyl 2,6-Bis(trifluoromethyl)-4-(trimethylsilyl)-3,5-pyridinedicarboxylate (Compound 31);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(methylthiomethylthio)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 33);
Methyl 5-(1-Bromo-2-methoxyethenyl)-4-(cyclopropyl-methyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 35);
Methyl 5-(Chloroethylthio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 44);
Methyl 4-(i-Propoxy)-5-{[3-(methoxycarbonyl)-4-(i-propoxy-)-6-(trifluoromethyl)-5-pyridyl]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 54);
Methyl 2-(Difluoromethyl)-4-cyclobutyl-5-(1-pyrrolyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 70);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(aminothionocarbonyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 77);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(dimethylamino)carbonyl]thiomethyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 79);
Methyl 2-(Difluoromethyl)-5-[(diethylphosphono)carbonyl]-4-(i-propylamino)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 85);
Dimethyl 2,6-Bis(methoxymethyl)-4-propyl-3,5-pyridinecarboxylate (Compound 92);
Methyl 5-[(Aminocarbonyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 145);
Methyl 2-(Difluoromethyl)-5-(1-ethoxyethylthio)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 146);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(1-methoxyethylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 147);
Methyl 2-(Difluoromethyl)-5-(2-fluoroethylthio)4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 148);
Methyl 5-(Acetylthio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 149);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(2-tetrhydrofurylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 150);
Methyl 2-(Difluoromethyl)-5-{[(3,5-di-t-butylphenyl)thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 151);
Methyl 2-(Difluoromethyl)-5-{[(2,4-dimethylphenyl)thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 152);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-methoxyphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 153);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(3-methoxyphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 154);
Methyl 2-(Difluoromethyl)-5-{[(2,4-di-t-butylphenyl)thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 155);
Methyl 5-{[(4-t-Butylphenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 156);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-isopropylphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 157);
Methyl 2-(Difluoromethyl)-5-{[(3,5-dimethylphenyl)thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 158);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(4-methylthiophenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 159);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-(4-fluorobenzyl)-4-isopropylphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 160);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-(4-fluorobenzyl)-4-fluorophenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 161);
Methyl 5-{[(4-chlorophenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 162);
Methyl 5-{[(2,5-Dichlorophenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 163);
Methyl 5-{[(2,6-Dichlorophenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 164);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-naphthyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 178);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(1-naphthyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 179);
3-Methyl 5-(3-Methoxyphenyl)2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridi-carboxylate (Compound 165);
3-Methyl 5-(2-Nitrophenyl)2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridi-carboxylate (Compound 166);
3-Methyl 5-(3,5-Di-t-butylphenyl)2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 167);
3-Methyl 5-(2,4-Di-t-butylphenyl)2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 168);
3-Methyl 5-(4-t-Butylphenyl)2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridi-carboxylate (Compound 169);
3-Methyl 5-[2-(4-Fluorobenzyl)-4-isopropylphenyl]2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 170);
3-Methyl 5-[2-(4-Fluorobenzyl)-3,4,5-(trimethoxy)phenyl]2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 171);
3-Methyl 5-(2-Methoxyphenyl)2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridi-carboxylate (Compound 172);
3-Methyl 5-(4-Chlorophenyl)2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridi-carboxylate (Compound 173);
3-Methyl 5-(3,5-Dimethylphenyl)2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridi-carboxylate (Compound 174);
3-Methyl 5-(2-Isopropylphenyl)2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridi-carboxylate (Compound 175);
3-Methyl 5-(2,6-Dimethyl-4-nitrophenyl)2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 176);
3-Methyl 5-(2,4-Dimethylphenyl)2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 177);
Methyl 5-(4-t-Butylphenyldithio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 180);
Dimethyl 5,5xe2x80x2-Dithiobis[2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate] (Compound 181);
Methyl 5-{[2-(Difluoromethyl)-4-(2-methylpropyl) -3-(methoxycarbonyl)-6-(trifluoromethyl)-5-pyridyl]methylthio}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 182);
Methyl 5-{[2-(Difluoromethyl)-4-(2-methylpropyl)-3-(methoxycarbonyl)-6-(trifluoromethyl)-5-pyridyl]carbonylthio}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 183);
Methyl 5-[(3-Bromophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 184);
Methyl 5-[(4-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 185);
Methyl 5-[(2,3,5,6-Tetrafluorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 186);
Methyl 5-[(3,5-Di-t-butylphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 187);
Methyl 5-[(1-Methylimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 188);
Methyl 5-[(1-Methyltetrazol-5-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 189);
Methyl 5-[(5-Nitrobenzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 190);
Methyl 5-[(4-(Trifluoromethoxy)phenyl))thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 191);
Methyl 5-[(Quinolin-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 192);
Methyl 5-[(4-Bromophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 193);
Methyl 5-[(Pentafluorophenyl)thiomethyl]-2-(difluoro-methyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 194);
Methyl 5-[(2,5-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 195);
Methyl 5-[(2,3,5,6-Tetrafluoro-4-(trifluoromethyl)phenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 196);
Methyl 5-[(4-Methylpyrimidin-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 197);
Methyl 5-[(4-Nitrophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 198);
Methyl 5-[(4-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 199);
Methyl 5-[(2-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 200);
Methyl 5-[(2,6-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 201);
Methyl 5-[(Quinolin-8-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 202);
Methyl 5-[(Pyrimidin-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 203);
Methyl 5-[(4-(Acetylamino)phenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 204);
Methyl 5-[(Benzoxazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 205);
Methyl 5-[(4-Bromo-2-(trifluoromethoxy)phenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 206);
Methyl 5-[(3-Aminophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 207);
Methyl 5-[(2-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 208);
Methyl 5-[(5-Methylbenzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 209);
Methyl 5-[(Benzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 210);
Methyl 5-[(3-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 211);
Methyl 5-[(Benzothiazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 212);
Methyl 5-[(3-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 213);
Methyl 5-[(3,4-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 214);
Methyl 5-[(2-Naphthyl)thiomethyll-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 215);
Methyl 5-[(2-Pyridyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 216);
Methyl 5-[(2-bromophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 217);
Bis{3-(carbomethoxy)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-5-pyridyl]methyl Sulfide (Compound 218);
Methyl 5-[(2-Chloro-3,4-methylenedioxyphenyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 226);
Methyl 5-[(2-pyridyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 233);
Methyl 5-[(2-quinolinyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 241);
Methyl 5-[(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)methylthio]-2-(difluoromethyl)-4-(2-methyl-propyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 245);
Methyl 5[(6-chloro-1,3-benzodioxan-8-yl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 246);
Diethyl 5,5xe2x80x2-(Carbonyldiimino)bis[6(difluoromethyl)-4-ethyl-2-(trifluoromethyl)-3-pyridinecarboxylate (Compound 48);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(dimethylamino)thiono]thiomethyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 43);
2-(Difluoromethyl)-5-hydroxymethyl-4-phenyl-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]hydroxymethyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-phenyl-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]hydroxymethyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]fluoromethyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]fluoromethyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-(2-naphthylfluoromethyl)pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]mercaptomethyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-phenyl-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]mercaptomethyl}pyridine;
2-(Cyclopentyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;
2-(1-Pyrrolidinyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;
2-(1-Pyrrolidinyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]hydroxymethyl}pyridine; and
2-(1-Pyrrolidinyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]fluoromethyl}pyridine.
In yet another embodiment, the method comprises the administration of a therapeutically effective amount of the compound of Formula IA which is selected from the compounds disclosed below:
Methyl 5-(4-t-Butylphenyldithio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Dimethyl 5,5xe2x80x2-Dithiobis[2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-[(3,4-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 2-(Difluoromethyl)-5-isothiocyanato-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-[(2-Naphthyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine carboxylate;
Methyl 2-(difluoromethyl)-5-mercapto-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
5-Ethyl 3-Methyl 2-(difluoromethyl)-4-[(4,5-dihydro-2-thiazolyl)thio]-6-(trifluoromethyl)-3,5-pyridinedicarboxylate;
Methyl 5-[(4-Nitrophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(palmitoylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 2-(Difluoromethyl)-5-(methoxycarbonylthio)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-[(4-t-Butylphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl))-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 2-(Difluoromethyl)-5-[(1,4-dithian-2-ylidene)amino]-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-[(4-(Trifluoromethoxy)phenyl))thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-[(4-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-[(5-Methylbenzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-[(Benzothiazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-[(3-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-{[3-(Carbomethoxy)-2-(difluoromethyl)-4-isobutyl-6-(trifluoromethyl)-5-pyridyl]thiomethyl}-2-(difluoromethyl)-4-isobutyl-6-(trifluoromethyl)-3-pyridinecarboxylate;
Di-t-Butyl 2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate;
Methyl 5-[(4-Bromophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-[(2,3,5,6-Tetrafluoro-4-(trifluoromethyl) phenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-[(4-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-[(Benzoxazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-[(Benzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(4,5-dihydro-2-thiazoyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Ethyl 2,6-Bis(trifluoromethyl)-5-methyl-4-[4-(trifluoromethylphenyl)carbonyloxy]-3-pyridinecarboxylate;
Methyl 2-(Difluoromethyl)-5-[(i-propylthio)carbonyl]-4-(cyclobutyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 4-(4-i-Propylphenylthio)-5-methyl-6-(trifluoromethyl)-3-pyridinecarboxylate;
Methyl 5-[(5-Nitrobenzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate; and
In yet another embodiment, the method comprises the administration of a therapeutically effective amount of the compound of Formula IA which is Dimethyl 5,5xe2x80x2-dithiobis[2-difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate].
In still another embodiment, the method comprises the administration of a therapeutically effective amount of the compound of Formula IB: 
wherein:
R2 and R6 are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R2 and R6 is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;
R3 is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl
xe2x80x94CHO,
xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen, alkyl and cyanoalkyl; and 
xe2x80x83wherein
R15a is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy, and
R16a is selected from the group consisting of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, and heterocyclyl, arylalkoxy, trialkylsilyloxy;
R4 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino, diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl,
xe2x80x94OC(O)N(R8aR8b), wherein R8a and R8b are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,
xe2x80x94SO2R9, wherein R9 is selected from the group consisting of hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,
xe2x80x94OP(O)(OR10a)(OR10b), wherein R10a and R10b are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and
xe2x80x94OP(S)(OR11a)(OR11b), wherein R11a and R11b are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
R5 is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl, arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl, alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl, heterocyclyloxyalkenyl, cyano, hydroxymethyl,
xe2x80x94CO2R14,
wherein R14 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; 
xe2x80x83wherein
R15b is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy, and
R16b is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, and trialkylsilyloxy; 
wherein R17 and R18 are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; 
wherein R19 is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, xe2x80x94SR20, xe2x80x94OR21, and xe2x80x94R22CO2R23, wherein
R20 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl, alkylheteroarylamino, arylheteroarylamino,
R21 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;
R22 is selected from the group consisting of alkylene or arylene, and
R23 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
wherein R24 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, aralkenyl, and aralkynyl; 
wherein R25 is heterocyclylidenyl; 
wherein R26 and R27 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
wherein R28 and R29 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
wherein R30 and R31 are independently alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and 
wherein R32 and R33 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
wherein R36 is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl and heterocyclyl; 
wherein R37 and R38 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; 
xe2x80x83wherein
R39 is selected from the group consisting of hydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio, and
R40 is selected from the group consisting of haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy, heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio;
xe2x80x94Nxe2x95x90R41,
wherein R41 is heterocyclylidenyl; 
xe2x80x83wherein
R42 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and
R43 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, and haloheterocyclyl; 
wherein R44 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
xe2x80x94Nxe2x95x90Sxe2x95x90O;
xe2x80x94Nxe2x95x90Cxe2x95x90S;
xe2x80x94Nxe2x95x90Cxe2x95x90O;
xe2x80x94N3;
xe2x80x94SR45,
wherein R45 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl, aminocarbonylaryl, aminocarbonylheteroaryl, and aminocarbonylheterocyclyl, xe2x80x94SR46, and xe2x80x94CH2R47,
wherein R46 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and
R47 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; and 
xe2x80x83wherein
R48 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and
R49 is selected from the group consisting of alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl; 
wherein R50 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy; 
wherein R51 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl; and 
wherein R53 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;
or a pharmaceutically acceptable salt or tautomer thereof,
provided that when R5 is selected from the group consisting of heterocyclylalkyl and heterocyclylalkenyl, the heterocyclyl radical of the corresponding heterocyclylalkyl or heterocyclylalkenyl is other than a xcex4-lactone; and
provided that when R4 is aryl, heteroaryl or heterocyclyl, and one of R2 and R6 is trifluoromethyl, then the other of R2 and R6 is difluoromethyl.
Novel Compounds
The present invention also relates to a class of novel substituted pyridines which are beneficial in the therapeutic and prophylactic treatment of CTEP-mediated disorders (such as coronary artery disease) as given in Formula IIA: 
wherein:
R2 and R6 are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R2 and R6 is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;
R3 is selected from the group consisting of arylcarbonyl, heteroarylcarbonyl, hydroxymethyl, arylalkoxyalkyl, trialkylsilyloxyalkyl,
xe2x80x94CHO,
xe2x80x94CO2R7,
wherein R7 is selected from the group consisting of hydrogen and alkyl (preferably methyl or ethyl); and 
xe2x80x83wherein
R15a is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, and
R16a is selected from the group consisting of alkyl, haloalkyl, alkenyl, aryl and heteroaryl;
R4 is selected from the group consisting of hydrogen, hydroxy, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, alkoxy, thio, trialkylsilyl, alkylamino, and xe2x80x94OC(O)N(R8)2, wherein R8 is aryl;
R5 is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aralkyl, alkoxy, aryloxy, cycloalkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, arylcarbonyloxyalkyl, pyrrolyl, substituted pyrrolidinyl, hydroxymethyl, arylalkoxyalkyl, and trialkylsilyloxyalkyl,
xe2x80x94CO2R14,
wherein R14 is alkyl; 
xe2x80x83wherein
R15b is selected from the group consisting of hydroxy, halogen, alkoxy, and alkylthio, aroyloxy, and alkylsulfonyloxy, and
R16b is selected from the group consisting of alkyl, alkenyl, aryl, and heteroaryl; 
wherein R17 and R18 are independently alkyl; 
wherein R19 is aryl, heteroaryl, xe2x80x94SR20, and xe2x80x94OR21,
wherein R20 is selected from the group consisting of aryl, heteroaryl and aminoalkyl, and
R21 is selected from the group consisting of aryl and heteroaryl; 
wherein R24 is aralkyl (preferably halo-substituted aralkyl); 
wherein R28 and R29 are independently alkyl; 
wherein R30 and R31 are independently alkoxy;
xe2x80x94Cxe2x89xa1Cxe2x80x94Si(R36)3,
wherein R36 is alkyl; 
xe2x80x83wherein
R37 is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and
R38 is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio;
provided that when R37 is hydrogen, then R38 is selected from the group consisting of haloalkyl, cycloalkyl, and heterocyclylalkoxy; 
xe2x80x83wherein
R42 is selected from the group consisting of hydrogen and alkyl, and
R43 is substituted heteroaryl; 
wherein R44 is selected from the group consisting of aryl and heteroaryl;
xe2x80x94SR45,
wherein R45 is selected from the group consisting of haloalkyl, heterocyclyl, alkylthioalkyl, aminocarbonylalkyl, xe2x80x94SR46, and xe2x80x94CH2R47,
wherein R46 is selected from the group consisting of aryl (preferably substituted aryl) and heteroaryl (preferably substituted pyridyl), and
R47 is selected from the group consisting of methylenedioxyphenyl, pyridyl, quinolinyl, tetrahydronaphthyl and benzodioxanyl; 
xe2x80x83wherein
R48 is selected from the group consisting of hydrogen and alkyl, and
R49 is selected from the group consisting of alkoxy and haloalkyl; 
wherein R50 is selected from the group consisting of alkyl, alkoxy, and heteroaryl (preferably substituted heteroaryl); and 
wherein R51 is haloalkyl;
or a pharmaceutically acceptable salt or tautomer thereof,
provided that:
when R2 is selected from the group consisting of difluoromethyl and trifluoromethyl, R3 is selected from the group consisting of xe2x80x94CO2H, xe2x80x94CO2CH3 and xe2x80x94CO2C2H5, R5 is hydrogen, and R6 is selected from the group consisting of hydrogen and trifluoromethyl, then R4 is selected from the group consisting of cycloalkyl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, thio, trialkylsilyl, alkylamino, and xe2x80x94OC(O)N(R8)2, wherein R8 is aryl; provided further that when R2, R3 and R5 are as defined above, and R4 is alkoxy, then R6 is hydrogen;
when R2 is selected from the group consisting of fluorinated methyl and chlorofluorinated methyl, R3 is selected from the group consisting of hydroxymethyl and CO2R7, R5 is selected from the group consisting of hydroxymethyl and CO2R14, R6 is selected from the group consisting of fluorinated methyl and chlorofluorinated methyl, and R7 and R14 are independently alkyl, then R4 is selected from the group consisting of hydrogen, thio, trialkylsilyl, and xe2x80x94OC(O)N(R8)2, wherein R8 is aryl;
when R2 is difluoromethyl, R3 is xe2x80x94CO2C2H5, R4 is hydrogen, R5 is xe2x80x94CO2C2H5, then R6 is selected from the group consisting of monofluoroalkyl, difluoroalkyl and alkoxyalkyl;
when R2 is trifluoromethyl, R3 is xe2x80x94CO2R7, R5 is methyl, R6 is selected from the group consisting of fluorinated methyl, fluorinated ethyl and chlorofluorinated methyl, and R7 is selected from the group consisting of hydrogen and alkyl, then R4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, thio, trialkylsilyl, and xe2x80x94OC(O)N(R8)2, wherein R8 is aryl; and
when R4 is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl, R3 is xe2x80x94CO2R7, and R7 is alkyl, then R5 is other than arylcarbonyl, heteroarylcarbonyl or 
wherein R16b is alkyl when R15b is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, or wherein R16b is aryl or heteroaryl when R15b is hydroxy;
when R4 is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl, R5 is xe2x80x94CO2R14, and R14 is alkyl, then R3 is other than arylcarbonyl, heteroarylcarbonyl or 
wherein R16a is alkyl when R15a is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, or wherein R16a is aryl or heteroaryl when R15a is hydroxy; and
when R2 and R6 are independently selected from fluorinated methyl and chlorofluorinated methyl, R3 is CO2R7, R5 is hydroxy, alkoxy or aryloxy, then R4 is selected from the group consisting of aryl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, thio, trialkylsilyl, alkylamino, and xe2x80x94OC(O)N(R8)2, wherein R8 is aryl; and
when R4 is aryl and one of R2 and R6 is trifluoromethyl, then the other of R2 and R6 is difluoromethyl.
In one embodiment, the novel compounds comprise a compound of Formula IIA as described above wherein:
R2 is fluorinated methyl; and
R3 is xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen, methyl and ethyl.
The compounds of Formula IIA are capable of inhibiting the activity of cholesteryl ester transfer protein (CETP), and thus could be used in the manufacture of a medicament or a method for the prophylactic or therapeutic treatment of diseases mediated by CETP, such as coronary artery disease, peripheral vascular disease, hyperlipidemia, hypercholesterolemia, and other diseases attributable to either high LDL and low HDL or a combination of both. The compounds of Formula IIA would be also useful in prevention of cerebral vascular accident (CVA) or stroke.
In another embodiment, the novel compounds comprise a compound of Formula IIA wherein:
R2 is fluorinated alkyl;
R3 is xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen and alkyl;
R4 is selected from the group consisting of alkyl and cycloalkyl;
R5 is selected from the group consisting of:
1-pyrrolyl; 
xe2x80x83wherein
R37 is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and
R38 is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio;
provided that when R37 is hydrogen, then R38 is selected from the group consisting of haloalkyl, cycloalkyl, and heterocyclylalkoxy; 
xe2x80x83wherein
R42 is selected from the group consisting of hydrogen and alkyl, and
R43 is substituted heteroaryl; 
wherein R44 is pyridyl; and
R6 is fluorinated alkyl;
or a pharmaceutically acceptable salt or tautomer thereof.
In yet another embodiment, the novel compounds comprise a compound of Formula IIA wherein:
R2 is fluorinated alkyl;
R3 is xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen and alkyl;
R4 is alkyl;
R5 is selected from the group consisting of:
xe2x80x94SR45 
wherein R45 is selected from the group consisting of haloalkyl, heterocyclyl, aralkyl, heteroaralkyl, alkylthioalkyl, aminocarbonylalkyl, xe2x80x94SR46, and xe2x80x94CH2R47,
wherein R46 is selected from the group consisting of aryl (preferably substituted aryl) and heteroaryl (preferably substituted pyridyl), and
R47 is selected from the group consisting of methylenedioxyphenyl, pyridyl, quinolinyl, tetrahydronaphthyl and benzodioxanyl; and 
xe2x80x83wherein
R48 is selected from the group consisting of hydrogen and alkyl, and
R49 is selected from the group consisting of alkoxy and haloalkyl; 
wherein R50 is selected from the group consisting of alkyl, alkoxy, and heteroaryl (preferably substituted heteroaryl); 
wherein R51 is haloalkyl; and
R6 is fluorinated alkyl;
or a pharmaceutically acceptable salt or tautomer thereof.
In yet another embodiment, the novel compounds comprise a compound of Formula IIA wherein:
R2 is fluorinated alkyl;
R3 is xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen and alkyl;
R4 is hydroxy, alkoxy, xe2x80x94OC(O)N(R8)2, or xe2x80x94OP(O)(OR10)2, wherein R8 is aryl and R10 is alkyl;
R5 is selected from the group consisting of hydrogen, alkoxy and aryloxy; and
R6 is selected from the group consisting of hydrogen and fluorinated alkyl;
or a pharmaceutically acceptable salt or tautomer thereof;
provided that when R2 is trifluoromethyl, R3 is selected from the group consisting of xe2x80x94CO2CH3 and xe2x80x94CO2C2H5, R5 is hydrogen, and R6 is selected from the group consisting of hydrogen and trifluoromethyl, then R4 is selected from the group consisting of alkoxy, xe2x80x94OC(O)N(R8)2, or xe2x80x94OP(O)(OR10)2, wherein R8 is aryl and R10 is alkyl; provided further that when R2, R3 and R5 are as defined above, and R4 is alkoxy, then R6 is hydrogen.
In yet another preferred embodiment, the novel compounds comprise a compound of Formula IIA wherein:
R2 is fluorinated alkyl;
R3 is xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen and alkyl;
R4 is selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, arylthio (preferably substituted arylthio), and alkylamino; and
R5 is selected from the group consisting of alkyl, arylcarbonyloxyalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl (preferably halo-substituted alkoxyalkenyl and more preferably bromo-substituted alkoxyalkenyl), substituted pyrrolidinyl, 
wherein R15 is alkoxy, and R16 is heteroaryl; 
wherein R17 and R18 are independently alkyl; 
wherein R19 is selected from the group consisting of pyridyl, xe2x80x94SR20, and xe2x80x94OR21, wherein R20 is selected from the group consisting of aryl, heteroaryl and aminoalkyl, and R21 is selected from the group consisting of aryl and heteroaryl; 
wherein R24 is aralkyl (preferably halo-substituted aralkyl); 
wherein R26 and R27 are independently alkyl; 
wherein R28 and R29 are independently alkoxy; and
xe2x80x94Cxe2x89xa1Cxe2x80x94Si(R10)3,
wherein R10 is alkyl; and
R6 is selected from the group consisting of hydrogen and fluorinated alkyl;
or a pharmaceutically acceptable salt or tautomer thereof;
provided that:
when R2 is trifluoromethyl, R3 is xe2x80x94CO2C2H5, R4 is iso-propoxy, R5 is methyl, then R6 is hydrogen; and
when R5 is alkyl, then R4 is selected from the group consisting of cycloalkyl, cycloalkylalkyl, arylthio, and alkylamino.
In yet another embodiment, the novel compounds comprise a compound of Formula IIA wherein:
R2 is selected from the group consisting of fluorinated alkyl and alkoxyalkyl;
R3 is xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen and alkyl;
R4 is selected from the group consisting of hydrogen, hydroxy, alkyl, heteroarylalkyl, thio, and trialkylsilyl;
R5 is CO2R14, wherein R14 is alkyl; and
R6 is selected from the group consisting of hydrogen, fluorinated alkyl, and alkoxyalkyl;
or a pharmaceutically acceptable salt or tautomer thereof;
provided that when R2 is difluoromethyl, R3 is xe2x80x94CO2C2H5, R4 is hydrogen, R5 is CO2C2H5, then R6 is selected from the group consisting of hydrogen, monofluoroalkyl, and difluoroalkyl.
In yet another embodiment, the novel compounds are compounds of Formula IIA wherein:
R2 is selected from the group consisting of alkyl and fluorinated alkyl;
R3 is selected from the group consisting of xe2x80x94CO2R7, wherein R7 is selected from the group consisting of hydrogen and alkyl;
R4 is selected from the group consisting of alkyl and thio;
R5 is selected from the group consisting of heterocyclyl, arylthioalkyl, heteroarylthioalkyl,
xe2x80x94C2R14,
wherein R14 is alkyl; 
xe2x80x83wherein
R39 is alkoxy, and
R40 is haloalkyl;
xe2x80x94SR45,
wherein R45 is selected from the group consisting of hydrogen, xe2x80x94SR46, and xe2x80x94CH2R47,
wherein R46 is selected from the group consisting of aryl and heteroaryl, and
R47 is selected from the group consisting of methylenedioxyphenyl, pyridyl, quinolinyl, naphthyl and benzodioxanyl; and 
wherein R50 is selected from the group consisting of alkyl and alkoxy; and
R6 is selected from the group consisting of alkyl and fluorinated alkyl;
or a pharmaceutically acceptable salt or tautomer thereof,
provided that when R2 is trifluoromethyl, R3 is CO2CH3, R4 is isobutyl, and R5 is CO2CH3, then R6 is selected from the group consisting of alkyl comprising at least two carbon atoms and fluorinated alkyl.
In yet another embodiment, the novel compounds of Formula IIA are selected from the compounds listed below:
Methyl 5-[(4-t-Butylphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl))-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 180);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(palmitoylthio)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 5);
Methyl 2-(Difluoromethyl)-5-(methoxycarbonylthio)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 6);
Diethyl 2,6-Bis(trifluoromethyl)-4-(trimethylsilyl)-3,5-pyridinedicarboxylate (Compound 31);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(methylthiomethylthio)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 33);
Methyl 5-(1-Bromo-2-methoxyethenyl)-4-(cyclopropyl-methyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 35);
Methyl 5-(Chloroethylthio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 44);
Methyl 4-(i-Propoxy)-5-{[3-(methoxycarbonyl)-4-(i-propoxy-)-6-(trifluoromethyl)-5-pyridyl]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 54);
Methyl 2-(Difluoromethyl)-4-cyclobutyl-5-(1-pyrrolyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 70);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(aminothionocarbonyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 77);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(dimethylamino)carbonyl]thiomethyl}-6-(trifluoro-methyl)-3-pyridinecarboxylate (Compound 79);
Methyl 2-(Difluoromethyl)-5-[(diethylphosphono)carbonyl]-4-(i-propylamino)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 85);
Dimethyl 2,6-Bis(methoxymethyl)-4-propyl-3,5-pyridinecarboxylate (Compound 92);
Methyl 5-[(Aminocarbonyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 145);
Methyl 2-(Difluoromethyl)-5-(1-ethoxyethylthio)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 146);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(1-methoxyethylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 147);
Methyl 2-(Difluoromethyl)-5-(2-fluoroethylthio)4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 148);
Methyl 5-(Acetylthio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 149);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(2-tetrhydrofurylthio)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 150);
Methyl 2-(Difluoromethyl)-5-{[(3,5-di-t-butylphenyl)thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 151);
Methyl 2-(Difluoromethyl)-5-{[(2,4-dimethylphenyl)thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 152);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-methoxyphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 153);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(3-methoxyphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 154);
Methyl 2-(Difluoromethyl)-5-{[(2,4-di-t-butylphenyl)thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 155);
Methyl 5-{[(4-t-Butylphenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 156);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-isopropylphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 157);
Methyl 2-(Difluoromethyl)-5-{[(3,5-dimethylphenyl)thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 158);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(4-methylthiophenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 159);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-(4-fluorobenzyl)-4-isopropylphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 160);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-(4-fluorobenzyl)-4-fluorophenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 161);
Methyl 5-{[(4-chlorophenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 162);
Methyl 5-{[(2,5-Dichlorophenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 163);
Methyl 5-{[(2,6-Dichlorophenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 164);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-naphthyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 178);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(1-naphthyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 179);
3-Methyl 5-(3-Methoxyphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 165);
3-Methyl 5-(2-Nitrophenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 166);
3-Methyl 5-(3,5-Di-t-butylphenyl) 2-(Difluoro-methyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 167);
3-Methyl 5-(2,4-Di-t-butylphenyl) 2-(Difluoro-methyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 168);
3-Methyl 5-(4-t-Butylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 169);
3-Methyl 5-[2-(4-Fluorobenzyl)-4-isopropylphenyl]2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoro-methyl)-3,5-pyridicarboxylate (Compound 170);
3-Methyl 5-[2-(4-Fluorobenzyl)-3,4,5-(trimethoxy)phenyl]2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 171);
3-Methyl 5-(2-Methoxyphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 172);
3-Methyl 5-(4-Chlorophenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 173);
3-Methyl 5-(3,5-Dimethylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 174);
3-Methyl 5-(2-Isopropylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 175);
3-Methyl 5-(2,6-Dimethyl-4-nitrophenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 176);
3-Methyl 5-(2,4-Dimethylphenyl) 2-(Difluoro-methyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 177);
Methyl 5-(4-t-Butylphenyldithio)-2-(difluoro-methyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 180);
Dimethyl 5,5xe2x80x2-Dithiobis[2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate] (Compound 181);
Methyl 5-{[2-(Difluoromethyl)-4-(2-methylpropyl)-3-(methoxycarbonyl)-6-(trifluoromethyl)-5-pyridyl]methylthio}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 182);
Methyl 5-{[2-(Difluoromethyl)-4-(2-methylpropyl)-3-(methoxycarbonyl)-6-(trifluoromethyl)-5-pyridyl]carbonylthio}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 183);
Methyl 5-[(3-Bromophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 184);
Methyl 5-[(4-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 185);
Methyl 5-[(2,3,5,6-Tetrafluorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoro-methyl)-3-pyridinecarboxylate (Compound 186);
Methyl 5-[(3,5-Di-t-butylphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 187);
Methyl 5-[(1-Methylimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 188);
Methyl 5-[(1-Methyltetrazol-5-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 189);
Methyl 5-[(5-Nitrobenzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 190);
Methyl 5-[(4-(Trifluoromethoxy)phenyl))thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoro-methyl)-3-pyridinecarboxylate (Compound 191);
Methyl 5-[(Quinolin-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 192);
Methyl 5-[(4-Bromophenyl)thiomethyl]-2-(difluoro-methyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 193);
Methyl 5-[(Pentafluorophenyl)thiomethyl]-2-(difluoro-methyl)-4-(2-methylpropyl)-6-(trifluoro-methyl)-3-pyridinecarboxylate (Compound 194);
Methyl 5-[(2,5-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoro-methyl)-3-pyridinecarboxylate (Compound 195);
Methyl 5-[(2,3,5,6-Tetrafluoro-4-(trifluoromethyl)phenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 196);
Methyl 5-[(4-Methylpyrimidin-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 197);
Methyl 5-[(4-Nitrophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 198);
Methyl 5-[(4-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 199);
Methyl 5-[(2-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 200);
Methyl 5-[(2,6-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 201);
Methyl 5-[(Quinolin-8-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 202);
Methyl 5-[(Pyrimidin-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 203);
Methyl 5-[(4-(Acetylamino)phenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 204);
Methyl 5-[(Benzoxazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 205);
Methyl 5-[(4-Bromo-2-(trifluoromethoxy)phenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 206);
Methyl 5-[(3-Aminophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 207);
Methyl 5-[(2-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 208);
Methyl 5-[(5-Methylbenzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 209);
Methyl 5-[(Benzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 210);
Methyl 5-[(3-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 211);
Methyl 5-[(Benzothiazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 212);
Methyl 5-[(3-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 213);
Methyl 5-[(3,4-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 214);
Methyl 5-[(2-Naphthyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 215);
Methyl 5-[(2-Pyridyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate (Compound 216);
Methyl 5-[(2-bromophenyl)thiomethyl]-2-(difluoro-methyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 217);
Bis{3-(carbomethoxy)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-5-pyridyl]methyl Sulfide (Compound 218);
Methyl 5-[(2-Chloro-3,4-methylenedioxyphenyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 226);
Methyl 5-[(2-pyridyl)methylthio]-2-(difluoro-methyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 233);
Methyl 5-[(2-quinolinyl)methylthio]-2-(difluoro-methyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 241);
Methyl 5-[(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 245); and
Methyl 5[(6-chloro-1,3-benzodioxan-8-yl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoro-methyl)-3-pyridinecarboxylate (Compound 246);
Diethyl 5,5,xe2x80x2-(Carbonyldiimino)bis[6(difluoromethyl)-4-ethyl-2-(trifluoromethyl)-3-pyridinecarboxylate (Compound 48);
Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(dimethylamino)thiono]thiomethyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 43);
2-(Difluoromethyl)-5-hydroxymethyl-4-phenyl-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]hydroxymethyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-phenyl-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]hydroxymethyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]fluoromethyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-([4-(trifluoromethyl)phenyl]fluoromethyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-(2-naphthylfluoromethyl)pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]mercaptomethyl}pyridine;
2-(Difluoromethyl)-5-hydroxymethyl-4-phenyl-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]mercaptomethyl}pyridine;
2-(Cyclopentyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;
2-(1-Pyrrolidinyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;
2-(1-Pyrrolidinyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]hydroxymethyl}pyridine; and
2-(1-Pyrrolidinyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]fluoromethyl}pyridine.
In yet another embodiment, the compound of Formula IA is Dimethyl 5,5xe2x80x2-dithiobis[2-difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate].
In another embodiment, the novel compounds comprise a compound of Formula IIB: 
wherein:
R2 and R6 are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R2 and R6 is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;
R3 is selected from the group consisting of arylcarbonyl, heteroarylcarbonyl, hydroxymethyl, arylalkoxyalkyl, trialkylsilyloxyalkyl,
xe2x80x94CHO,
xe2x80x94CO2R7,
wherein R7 is selected from the group consisting of hydrogen and alkyl; and 
xe2x80x83wherein
R15a is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, and
R16a is selected from the group consisting of alkyl, haloalkyl, alkenyl, aryl and heteroaryl;
R4 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, alkoxy, thio, trialkylsilyl, alkylamino, and xe2x80x94OC(O)N(R8)2, wherein R8 is aryl;
R5 is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aralkyl, alkoxy, aryloxy, cycloalkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, arylcarbonyloxyalkyl, pyrrolyl, substituted pyrrolidinyl, hydroxymethyl, arylalkoxyalkyl, and trialkylsilyloxyalkyl,
xe2x80x94CO2R14,
wherein R14 is alkyl; 
xe2x80x83wherein
R15b is selected from the group consisting of hydroxy, halogen, alkoxy, and alkylthio, aroyloxy, and alkylsulfonyloxy, and
R16b is selected from the group consisting of alkyl, alkenyl, aryl, and heteroaryl; 
wherein R17 and R18 are independently alkyl; 
wherein R19 is aryl, heteroaryl, xe2x80x94SR20, and xe2x80x94OR21,
wherein R20 is selected from the group consisting of aryl, heteroaryl and aminoalkyl, and
R21 is selected from the group consisting of aryl and heteroaryl; 
wherein R24 is aralkyl; 
wherein R28 and R29 are independently alkyl; 
wherein R30 and R31 are independently alkoxy;
xe2x80x94Cxe2x89xa1Cxe2x80x94Si(R36)3,
wherein R36 is alkyl; 
xe2x80x83wherein
R37 is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and
R38 is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio;
provided that when R37 is hydrogen, then R38 is selected from the group consisting of haloalkyl, cycloalkyl, and heterocyclylalkoxy; 
xe2x80x83wherein
R42 is selected from the group consisting of hydrogen and alkyl, and
R43 is substituted heteroaryl; 
wherein R44 is selected from the group consisting of aryl and heteroaryl;
xe2x80x94SR45,
wherein R45 is selected from the group consisting of haloalkyl, heterocyclyl, alkylthioalkyl, aminocarbonylalkyl, xe2x80x94SR46, and xe2x80x94CH2R47,
wherein R46 is selected from the group consisting of aryl and heteroaryl, and
R47 is selected from the group consisting of methylenedioxyphenyl, pyridyl, quinolinyl, tetrahydronaphthyl and benzodioxanyl; 
xe2x80x83wherein
R48 is selected from the group consisting of hydrogen and alkyl, and
R49 is selected from the group consisting of alkoxy and haloalkyl; 
wherein R50 is selected from the group consisting of alkyl, alkoxy, and heteroaryl; and 
wherein R51 is haloalkyl;
or a pharmaceutically acceptable salt or tautomer thereof,
provided that:
when R2 is selected from the group consisting of difluoromethyl and trifluoromethyl, R3 is selected from the group consisting of xe2x80x94CO2H, xe2x80x94CO2CH3 and xe2x80x94CO2C2H5, R5 is hydrogen, and R6 is selected from the group consisting of hydrogen and trifluoromethyl, then R4 is selected from the group consisting of cycloalkyl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, thio, trialkylsilyl, alkylamino, and xe2x80x94OC(O)N(R8)2, wherein R8 is aryl; provided further that when R2, R3 and R5 are as defined above, and R4 is alkoxy, then R6 is hydrogen;
when R2 is selected from the group consisting of fluorinated methyl and chlorofluorinated methyl, R3 is selected from the group consisting of hydroxymethyl and CO2R7, R5 is selected from the group consisting of hydroxymethyl and CO2R14, R6 is selected from the group consisting of fluorinated methyl and chlorofluorinated methyl, and R7 and R14 are independently alkyl, then R4 is selected from the group consisting of thio, trialkylsilyl, and xe2x80x94OC(O)N(R8)2, wherein R8 is aryl;
when R2 is difluoromethyl, R3 is xe2x80x94CO2C2H5, R4 is hydrogen, R5 is xe2x80x94CO2C2H5, then R6 is selected from the group consisting of hydrogen, monofluoroalkyl, difluoroalkyl and alkoxyalkyl;
when R2 is trifluoromethyl, R3 is xe2x80x94CO2R7, R5 is methyl, R6 is selected from the group consisting of fluorinated methyl, fluorinated ethyl and chlorofluorinated methyl, and R7 is selected from the group consisting of hydrogen and alkyl, then R4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, thio, trialkylsilyl, and xe2x80x94OC(O)N(R8)2, wherein R8 is aryl;
when R4 is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl, R3 is xe2x80x94CO2R7, and R7 is alkyl, then R5 is other than arylcarbonyl, heteroarylcarbonyl or 
wherein R16b is alkyl when R15b is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, or wherein R16b is aryl or heteroaryl when R15b is hydroxy;
when R4 is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl, R5 is xe2x80x94CO2R14, and R14 is alkyl, then R3 is other than arylcarbonyl, heteroarylcarbonyl or 
wherein R16a is alkyl when R15a is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, or wherein R16a is aryl or heteroaryl when R15a is hydroxy; and
when R2 and R6 are independently selected from fluorinated methyl and chlorofluorinated methyl, R3 is CO2R7, R5 is hydroxy, alkoxy or aryloxy, then R4 is selected from the group consisting of aryl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, thio, trialkylsilyl, alkylamino, and xe2x80x94OC(O)N(R8)2, wherein R8 is aryl; and
when R4 is aryl and one of R2 and R6 is trifluoromethyl, then the other of R2 and R6 is difluoromethyl.
Additional Compounds
Additional novel compounds that could be used in the methods and compositions of the present invention include, but are not limited to, the compounds: 
and those compounds listed in Tables 9, 10, 11 and 12 below. These compounds could be prepared by appropriate modification of the synthetic schemes previously referenced in this application.
Pharmaceutical Compositions
Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of Formulae I, IA, IB and/or Formulae IIA or IIB in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as xe2x80x9ccarrierxe2x80x9d materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and compositions may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
The phrase xe2x80x9cco-therapyxe2x80x9d (or combination-therapy), in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent. The compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in co-therapy with one or more cardiovascular agents, such as compounds that lower serum cholesterol concentrations including inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors such as the statins (atorvastatin, cerivastatin, pravastatin, simvastatin, fluvastatin and lovastatin), inhibitors of squalene synthase, oxido squalene cyclase or inhibitors of other enzymes involved with cholesterol biosynthesis; inhibitors of the ileal bile acid transport protein (IBAT), cholesterol absorption antagonists, ACAT inhibitors, bile acid sequestrants such as Cholestyramine and Cholestagel, fibrates such as Gemfibrozil, niacins such as Niaspan, and omega-3 fatty acids such as Omacor. Compounds of the present invention can also be used in co-therapy with cardiovascular drugs that reduce hypertension such as Enalopril and Captopril, or with anti-diabetes drugs such as troglitazone, or with antithrombotic agents such as aspirin, warfarin, and glycoprotein IIbIIIa antagonists such as Reopro, Xemilofiban and Orbofiban. The compounds of this invention can also be used in co-therapy with agents which lower serum triglyceride concentrations, including inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors such as the statins (atorvastatin), fibrates such as Gemfibrozil, niacins such as Niaspan, and omega-3 fatty acids such as Omacor.
The phrase xe2x80x9ctherapeutically-effectivexe2x80x9d is intended to qualify the amount of each agent which will achieve the goal of improvement in disease severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely. Patients undergoing treatment with the compounds and/or compositions disclosed herein can be routinely monitored by conventional methods to determine the effectiveness of therapy. Continuous analysis of the data obtained permits modification of the treatment regimen during treatment so that optimal amounts of the compounds and/or compositions of this invention are administered, and so that the duration of treatment can be determined as well. Thus, the treatment regimen/dosing schedule can be rationally modified over the course of treatment so as to achieve the lowest doses of each of the compounds and/or compositions of-this invention which together result in satisfactory anti-lipidemic effectiveness, and so that administration of these compounds is continued only so long as is necessary to successfully treat the patient.
The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 2000 mg, and preferably in the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day.
The compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The antiinflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.
For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
Additional Substituted Pyridines
The present invention further includes a group of substituted pyridines which exhibit percentage transfers in excess of 100% and are useful (i) in examining the structural requirements of the active site of the CTEP molecule, (ii) as control pyridines in the study of the mechanism for inhibiting the activity of CETP, and (ii) in the design of substituted pyridines which are effective CTEP inhibitors. Accordingly, they are useful in studying the prevention and treatment of dyslipidemia (hypoalphalipoproteinaemia), hyperlipoproteinaemia (chylomicronemia and hyperapobetalipoproteinaemia), peripheral vascular disease, hypercholesterolemia, atherosclerosis, coronary artery disease and other CETP-mediated disorders. These substituted pyridines include those compounds listed in Table 13 below:
Definitions and Abbreviations
The use of generic terms and abbreviations in the description of the compounds are herein defined for clarity.
The term xe2x80x9calkylxe2x80x9d, either alone or within other terms such as xe2x80x9chaloalkylxe2x80x9d, xe2x80x9ccyanoalkylxe2x80x9d and xe2x80x9calkylthioxe2x80x9d, embraces substituted or unsubstituted linear or branched radicals having one to about 10 carbon atoms. More preferred alkyl radicals are xe2x80x9clower alkylxe2x80x9d radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and the like. The term xe2x80x9chigher alkylxe2x80x9d denotes linear or branched radicals having eleven to about twenty carbon atoms. Examples of such radicals include undecyl, dodecyl, tridecyl, tetradecyl, and pentadecyl.
The term xe2x80x9calkenylxe2x80x9d, either alone or within other terms such as xe2x80x9chaloalkenylxe2x80x9d and xe2x80x9calkenylthioxe2x80x9d, embraces substituted or unsubstituted linear or branched radicals having one to about 10 carbon atoms and having one or more double bonds. More preferred alkenyl radicals are xe2x80x9clower alkenylxe2x80x9d radicals having one to about six carbon atoms. Examples of such radicals include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. The term xe2x80x9chigher alkenylxe2x80x9d denotes linear or branched radicals having from 11 to about 20 carbon atoms and having one or more double bonds. Examples of such radicals include undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl. Preferably, the unsaturation is remote from the moiety attaching the alkenyl group to the pyridine ring.
The term xe2x80x9calkynylxe2x80x9d, either alone or within other terms such as xe2x80x9chaloalkynylxe2x80x9d and xe2x80x9calkynylthioxe2x80x9d, embraces substituted or unsubstituted linear or branched radicals having one to about 10 carbon atoms and having one or more triple bonds. More preferred alkynyl radicals are xe2x80x9clower alkynylxe2x80x9d radicals having one to about six carbon atoms. Examples of such radicals include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. The term xe2x80x9chigher alkynylxe2x80x9d denotes linear or branched radicals having from 11 to about 20 carbon atoms having one or more triple bonds. Examples of such radicals include undecynyl, dodecynyl, tridecynyl, tetradecynyl, and pentadecynyl. Preferably, the unsaturation is remote from the moiety attaching the alkynyl group to the pyridine ring.
The term xe2x80x9carylxe2x80x9d, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term xe2x80x9carylxe2x80x9d embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane, anthryl and biphenyl. Said xe2x80x9carylxe2x80x9d group can be substituted or unsubstituted.
The term xe2x80x9cheterocyclylxe2x80x9d embraces saturated or partially saturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Partially saturated heterocyclyl radicals have at least one double bond, but less than the maximum number of double bonds possible for the heterocyclyl ring. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. azyrindinyl, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 oxygen atoms [e.g. oxiranyl, oxolanyl, dioxolanyl, dioxanyl, etc.]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 sulfur atoms [e.g. thiolanyl, dithiolanyl, dithianyl, etc.]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. oxazolidinyl, morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]; and saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 oxygen atoms [e.g., oxathiolanyl, etc.]. Examples of partially saturated heterocyclyl radicals include imidazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, dihydrothiophene, dihydropyran and dihydrofuran. Heterocyclic radicals also encompass unsaturated or partially saturated condensed heterocyclic radicals such as benzodioxanyl. Heterocyclyl radicals further can be unsubstituted or substituted with one or more groups including, for example, alkyl, halo, alkoxy, nitro, trifluoromethoxy, cycloalkyl, haloalkyl, alkylthio, alkylidene, acylamino, aryloxy, arylalkoxy, and oxo.
The term xe2x80x9cheteroarylxe2x80x9d embraces unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Heteroaryl radicals have the maximum number of double bonds possible for the heterocyclyl ring. Examples of heteroaryl radicals include unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, triazolyl, tetrazolyl, etc.; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl and benzotriazolyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl and isoxazolyl, etc.; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen 5 atoms, for example, thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said xe2x80x9cheterocyclylxe2x80x9d group may have 1 to 3 substituents such as, for example, lower alkyl, lower alkoxy, halo, hydroxy, oxo, amino and lower alkylamino. Preferred heterocyclic radicals include five to ten membered fused or unfused radicals. More preferred examples of heteroaryl radicals include pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Heteroaryl can be unsubstituted or substituted with one or more groups selected from, for example, alkyl, halo, alkoxy, nitro, trifluoro-methoxy, cycloalkyl, haloalkyl, alkylthio, alkylidene, acylamino, aryloxy, arylalkoxy, and oxo.
The term xe2x80x9ccycloalkylxe2x80x9d embraces substituted or unsubstituted radicals having three to ten carbon atoms. More preferred cycloalkyl radicals are xe2x80x9clower cycloalkylxe2x80x9d radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term xe2x80x9ccycloalkylalkylxe2x80x9d embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are xe2x80x9clower cycloalkylalkylxe2x80x9d radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclopropylmethyl and cyclohexylhexyl. Also preferred cycloalkylalkyl radicals are xe2x80x9chigher cycloalkylalkylxe2x80x9d radicals having cycloalkyl radicals attached to alkyl radicals having seven to fifteen carbon atoms. Examples of such radicals include cyclohexyldodecyl.
The term xe2x80x9ccycloalkenylxe2x80x9d embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds. More preferred cycloalkenyl radicals are xe2x80x9clower cycloalkenylxe2x80x9d radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. Said xe2x80x9carylxe2x80x9d group may have 1 to 3 substituents such as, for example, lower alkyl, alkoxy, halo, hydroxy, oxo, amino and lower alkylamino.
The term xe2x80x9caralkylxe2x80x9d embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are xe2x80x9clower aralkylxe2x80x9d radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. Also preferred aralkyl radicals are xe2x80x9chigher aralkylxe2x80x9d radicals having aryl radicals attached to alkyl radicals having seven to fifteen carbon atoms. Examples of such radicals include phenyloctyl and phenylundecyl. The aryl in said aralkyl may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The terms benzyl and phenylmethyl are used herein interchangeably.
The term xe2x80x9cheteroaralkylxe2x80x9d embraces heteroaryl-substituted alkyl radicals. Preferable heteroaralkyl radicals are xe2x80x9clower heteroaralkylxe2x80x9d radicals having heteroaryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include xe2x80x94CH(OH)-2-furyl; xe2x80x94CH(OH)-2-thienyl; xe2x80x94CH(OCH3)-2-thienyl; and xe2x80x94CH(OCH3)-(5-isothiazolyl). Also preferred heteroaralkyl radicals are xe2x80x9chigher heteroaralkylxe2x80x9d radicals having heteroaryl radicals attached to alkyl radicals having seven to fifteen carbon atoms. The heteroaryl in said heteroaralkyl may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9cheterocyclylalkylxe2x80x9d, embraces heterocyclyl-substituted alkyl radicals. Preferable heterocyclylalkyl radicals are xe2x80x9clower heterocyclylalkyxe2x80x9d, radicals having heterocyclyl radicals attached to alkyl radicals having one to six carbon atoms. An examples of such radicals is xe2x80x94CH2-(2-thiazolinyl). Also preferred heterocyclylalkyl radicals are xe2x80x9chigher heterocyclylalkylxe2x80x9d radicals having heterocyclyl radicals attached to alkyl radicals having seven to fifteen carbon atoms. The heterocyclyl radical in said heterocyclylalkyl may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9caralkenylxe2x80x9d embraces aryl-substituted alkenyl radicals. Preferable aralkenyl radicals are xe2x80x9clower aralkenylxe2x80x9d radicals having aryl radicals attached to alkenyl radicals having one to six carbon atoms. Examples of such radicals include xe2x80x94CHxe2x95x90C(CH3)Ph. Also preferred aralkenyl radicals are xe2x80x9chigher aralkenylxe2x80x9d radicals having aryl radicals attached to alkenyl radicals having seven to fifteen carbon atoms. The aryl in said aralkenyl may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9calkoxyxe2x80x9d embraces linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. More preferred alkoxy radicals are xe2x80x9clower alkoxyxe2x80x9d radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, iso-propoxy, butoxy and tert-butoxy. The xe2x80x9calkoxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkoxyxe2x80x9d radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
The term xe2x80x9caryloxyxe2x80x9d embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy. The aryl in said aryloxy may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term xe2x80x9caralkoxyxe2x80x9d embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are xe2x80x9clower aralkoxyxe2x80x9d radicals having phenyl radicals attached to lower alkoxy radical as described above. The aryl in said aralkoxy radicals may be additionally substituted with, for example halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9caryloxyalkylxe2x80x9d embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl. The aryl in said aryloxyalkyl may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9calkoxyalkylxe2x80x9d embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl. Also preferred alkoxyalkyl radicals are xe2x80x9chigher alkoxyalkylxe2x80x9d radicals having seven to fifteen carbon atoms. An example of xe2x80x9chigher alkoxyalkylxe2x80x9d is undecyloxymethyl.
The term xe2x80x9calkoxyalkenylxe2x80x9d embraces linear or branched alkenyl radicals having one or more alkoxy radicals attached to the alkenyl radical, that is, to form monoalkoxyalkenyl and dialkoxyalkenyl radicals. Preferred alkoxyalkenyl radicals are xe2x80x9clower alkoxyalkenylxe2x80x9d radicals having alkoxy radicals of six to fifteen carbon atoms. An examples of such radicals is xe2x80x94CHxe2x95x90CHOCH3. The xe2x80x9calkenylxe2x80x9d and/or xe2x80x9calkoxyxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkenylxe2x80x9d and/or xe2x80x9chaloalkoxyxe2x80x9d radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
The term xe2x80x9caralkoxyxe2x80x9d embraces alkoxy radicals having one or more aryl radicals attached to the alkoxy radical, that is, to form monoaralkoxy and diaralkoxy radicals. Preferred aralkoxy radicals are xe2x80x9clower aralkoxyxe2x80x9d radicals having alkoxy radicals of one to ten carbon atoms. Examples of such radicals include phenylmethoxy. The xe2x80x9carylxe2x80x9d and xe2x80x9calkoxyxe2x80x9d radicals may be further substituted with, for example, halogen, alkyl, haloalkyl, alkoxy, nitro, carboxy, carbalkoxy, alkylthio, alkylamino, dialkylamino, and amino. Examples of such radicals include, for example, methyl, chloro, trifluoromethyl, methoxy, xe2x80x94CO2H, xe2x80x94CO2C2H5, methylthio, methylamino and dimethylamino.
The term xe2x80x9cheteroaralkoxyxe2x80x9d embraces alkoxy radicals having one or more heteroaryl radicals attached to the alkoxy radical, that is, to form monoheteroaralkoxy and diheteroaralkoxy radicals. Preferred heteroaralkoxy radicals are xe2x80x9clower heteroaralkoxyxe2x80x9d radicals having alkoxy radicals of one to ten carbon atoms. Examples of such radicals include oxaranylmethoxy and 2-pyridylmethoxy. The xe2x80x9cheteroarylxe2x80x9d and xe2x80x9calkoxyxe2x80x9d radicals may be further substituted with, for example, halogen, alkyl, haloalkyl, alkoxy, nitro, carboxy, carbalkoxy, alkylthio, alkylamino, dialkylamino, and amino. Examples of such radicals include, for example, methyl, chloro, trifluoromethyl, methoxy, xe2x80x94CO2H, xe2x80x94CO2C2H5, methylthio, methylamino and dimethylamino.
The term xe2x80x9ccarbonylxe2x80x9d embraces the xe2x80x94C(O)xe2x80x94 radical found in such compounds as aldehydes and ketones.
The term xe2x80x9calkoxycarbonylxe2x80x9d embraces a carbonyl group, as defined above, having an attached alkoxy radical. Examples of such radicals include methoxycarbonyl and ethoxycarbonyl. The xe2x80x9calkoxyxe2x80x9d radicals may be further substituted with, for example, halogen and cyano. Examples of such radicals include fluoroethoxycarbonyl and cyanomethoxycarbonyl.
The term xe2x80x9carylcarbonyloxyxe2x80x9d embraces a carbonyl radical attached through an oxygen atom to other radicals and additionally having an aryl radical attached to the carbonyl group. More preferred arylcarbonyloxy radicals are xe2x80x9clower arylcarbonyloxyxe2x80x9d radicals having phenyl radicals attached to the carbonyl radical as described above, such as benzoyloxy. The aryl in said arylcarbonyloxy radicals may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9carylcarbonyloxyalkylxe2x80x9d embraces an arylcarbonyloxy radical, as defined above, attached to attached an alkyl radical. More preferred arylcarbonyloxyalkyl radicals are xe2x80x9clower arylcarbonyloxyalkylxe2x80x9d radicals wherein the aryl portion of the arylcarbonyloxyalkyl radical comprises one or more phenyl radicals attached to the carbonyl as described above, such as benzoyloxymethyl. The aryl in said arylcarbonyloxy radicals may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9cthioxe2x80x9d embraces radicals containing a divalent sulfur. An example of a thio radical is the sulfhydryl (or xe2x80x94SH) radical.
The term xe2x80x9calkylthioxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are xe2x80x9clower alkylthioxe2x80x9d radicals having one to six carbon atoms. Examples of xe2x80x9clower alkylthioxe2x80x9d include methylthio (xe2x80x94Sxe2x80x94CH3) and ethylthio (xe2x80x94Sxe2x80x94CH2CH3). Also preferred alkylthio radicals are xe2x80x9chigher alkylthioxe2x80x9d radicals having seven to fifteen carbon atoms. An example of xe2x80x9chigher alkylthioxe2x80x9d is dodecylthio.
The term xe2x80x9ccycloalkylthioxe2x80x9d embraces radicals containing a cyclic alkyl radical, of three to ten carbon atoms, attached to a divalent sulfur atom. More preferred cycloalkylthio radicals are xe2x80x9clower cycloalkylthioxe2x80x9d radicals having three to six carbon atoms. An example of xe2x80x9clower cycloalkylthioxe2x80x9d is cyclobutylthio. Also preferred cycloalkylthio radicals are xe2x80x9chigher cycloalkylthioxe2x80x9d radicals having seven to fifteen carbon atoms. An example of xe2x80x9chigher cycloalkylthioxe2x80x9d is cyclooctylthio.
The term xe2x80x9carylthioxe2x80x9d embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio. The aryl in said arylthio may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9cheteroarylthioxe2x80x9d embraces heteroaryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include pyridylthio. The heteroaryl in said heteroarylthio may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9calkylthioalkylxe2x80x9d embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl and ethylthioethyl. Also preferred alkylthioalkyl radicals are xe2x80x9chigher alkylthioalkylxe2x80x9d radicals having seven to fifteen carbon atoms. An example of xe2x80x9chigher alkylthioalkylxe2x80x9d is undecylthiomethyl.
The term xe2x80x9carylthioalkylxe2x80x9d embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl. The aryl in said arylthioalkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9cheteroarylthioalkylxe2x80x9d embraces heteroarylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyrimidinylthiomethyl. The heteroaryl in said heteroarylthioalkyl may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d means halogens such as fluorine, chlorine, bromine or iodine atoms. The term xe2x80x9chaloalkylxe2x80x9d embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are xe2x80x9clower haloalkylxe2x80x9d radicals having one to about six carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term xe2x80x9cchlorinated methylxe2x80x9d means a methyl group having one or more chlorine atoms bonded thereto, including a alkyl radical wherein all the hydrogen atoms are replaced by chlorine. The term xe2x80x9cfluorinated alkylxe2x80x9d means an alkyl group having one or more fluorine atoms bonded thereto, including a methyl radical wherein all the hydrogen atoms are replaced by fluorine. Fluorinated methyl is the preferred fluorinated alkyl. The term xe2x80x9cchlorofluorinated methylxe2x80x9d means a methyl group having a chloro atom and one or two fluorine atoms bonded thereto, including a methyl radical wherein all the hydrogen atoms are replaced by a chlorine atom and two fluorine atoms.
The term xe2x80x9camidoxe2x80x9d or xe2x80x9caminocarbonylxe2x80x9d embraces amino radicals attached to a carbonyl radicals. The amino radical in said amido radical may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9calkylaminoxe2x80x9d embraces an alkyl radical, as defined above, attached to an amino group. Examples of such alkylamino radicals include methylamino and ethylamino. The alkyl radical in said alkylamino radical may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term xe2x80x9ctrialkylsilylxe2x80x9d embraces silyl radicals tri-substituted with alkyl radicals. Examples of such trialkylsilyl radicals include trimethylsilyl and triethylsilyl. The alkyl radical in said trialkylsilyl radical may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The terms xe2x80x9ccisxe2x80x9d and xe2x80x9ctransxe2x80x9d denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond (xe2x80x9ccisxe2x80x9d) or on opposite sides of the double bond (xe2x80x9ctransxe2x80x9d).
In addition to those substitutions described above, the substituents of the substituted alkyl, alkenyl, alkynyl, aryl, and heteroaryl groups and other moieties described above include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, nitrogen, oxygen, sulfur, haloalkyl such as trifluoromethyl, lower alkoxy such as methoxy, ethoxy or butoxy, lower haloalkoxy, hydroxy, halogen such as chloro or fluoro, nitro, amino, and keto.
As used herein, xe2x80x9cPhxe2x80x9d means phenyl; xe2x80x9cMexe2x80x9d means methylxe2x80x9d; xe2x80x9cEtxe2x80x9d means ethyl; xe2x80x9cEthylidinexe2x80x9d means the group CH3CHxe2x95x90; xe2x80x9cRxe2x80x9d means alkyl unless otherwise defined; xe2x80x9cPrxe2x80x9d means propyl; xe2x80x9ci-Prxe2x80x9d means iso-propyl; xe2x80x9ci-propoxyxe2x80x9d means isopropoxy; xe2x80x9cc-Prxe2x80x9d means cyclopropyl; xe2x80x9cBuxe2x80x9d means butyl; xe2x80x9ci-Buxe2x80x9d means iso-butyl; xe2x80x9ct-Buxe2x80x9d means tert-butyl; xe2x80x9cc-Buxe2x80x9d means cyclobutyl; xe2x80x9cHxxe2x80x9d means hexyl; xe2x80x9cc-C5H9xe2x80x9d means cyclopentyl; xe2x80x9cc-Hxxe2x80x9d means cyclohexyl; xe2x80x9cBxe2x80x9d means boron; xe2x80x9cBrxe2x80x9d means bromine; xe2x80x9cCxe2x80x9d means carbon; xe2x80x9cClxe2x80x9d means chlorine; xe2x80x9cFxe2x80x9d means fluorine; xe2x80x9cHxe2x80x9d means hydrogen; xe2x80x9cIxe2x80x9d means iodine; xe2x80x9cNxe2x80x9d means nitrogen; xe2x80x9cOxe2x80x9d means oxygen; xe2x80x9cPxe2x80x9d means phosphorus; xe2x80x9cSxe2x80x9d means sulfur; xe2x80x9cSixe2x80x9d means silicon; and xe2x80x9cTBSxe2x80x9d means dimethyl-tert-butyl-silyl.
Preparation of Substituted Pyridines
A number of the substituted pyridine compounds and intermediates having pharmacological activity were previously known as herbicides. Accordingly, the specific and/or general procedures for preparing such known compounds can be found in U.S. Pat. Nos. 4,609,399, 4,655,816; 4,692,184; 4,698,093; 4,789,395; 4,885,026; 4,936,905; 4,988,384; 5,037,469; 5,125,961; 5,129,943; 5,156,670; 5,169,432; and 5,260,262; and in Chem. Pharm. Bull., 14, 918 (1966); Biokhimya, 33, 350 (1968); J. Agric Chem., 39, 2072 (1991); Ann., 246, 32 (1888); Res. Discl., 295, 867 (1988); and J. Heterocyclic Chem., 26, 1771 (1989). These references are incorporated herein by reference.
The xe2x80x9cProcedure Referencexe2x80x9d column of Tables 1-2 provides exemplary references disclosing the specific procedures for the preparation of many of the substituted pyridines identified in those Tables. These references are incorporated herein by reference. One skilled in the art can prepare these compounds based on the disclosure of the references. A reference to xe2x80x9cSee Example ___ xe2x80x9d indicates that the procedure, while not specifically for the preparation of the compound listed in the Table, is sufficiently analogous that one skilled in the art can prepare the compound by making the necessary modifications to the referenced procedure without undue experimentation. Additional information for the preparation of a number of these compounds also is set forth below. A written description of the procedures for preparing the remaining substituted pyridines for which no corresponding reference appears in the Tables is set forth below.
The 2,6-dimethyl- and 2,6-bis(methoxymethyl)-3,5-pyridinedicarboxylates (such as Compound 92 and Compound 106) can be prepared by the procedure described in Ann., 246, 32 (1888) and Ann., 241, 1 (1882).
The 5-mercapto analogs II (see, e.g., Example 2 below) can be prepared from the 5-bromo derivative I (which itself can be prepared as shown in U.S. Pat. No. 4,789,395) by reaction with lithium sulfide. The 5-mercapto analogs II can be converted to the disulfide III by oxidation or by reaction with a mixture of 2-fluoroethanol, methanesulfonyl chloride and triethylamine or by reaction with bromine in acetic acid. The 5-mercapto analogs can be reacted with alkyl halides and acyl halides to give the derivatives IV and V cited in this invention. Alternatively pyridyl methylchloride VI can be reacted with a thiol to give the sulfide VII (see, e.g., Example 22 below) 